Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets.

1. Introduction

According to the 2020 global cancer rating, liver cancer is the 6th most common cancer worldwide in incidence ( https://www.wcrf.org/cancer-trends/liver-cancer-statistics/ , accessed on 31 January 2024) and third in total cancer-related deaths ( https://gco.iarc.fr/today/ , accessed on 31 January 2024).

Histologically, two main subtypes of primary liver cancer can be distinguished, the most common subtype being hepatocellular carcinoma (HCC), with a 75–80% frequency, and the second most common being intrahepatic cholangiocarcinoma with a 10–15% frequency [ 1 ].

HCC has a strong association with chronic viral hepatitis, caused by hepatitis B and C virus infections (HBV and HCV, respectively) [ 2 ]. Other risk factors for HCC onset are non-viral chronic hepatitis (e.g., alpha-1-antitrypsin deficiency, hereditary hemochromatosis, and glycogen storage disease); alcohol-abuse-related steatosis; nonalcoholic steatohepatitis (NASH); environmental exposure to aflatoxin B1; and cigarette smoking [ 3 ]. No specific genetic alterations have been unequivocally associated with liver cancer tumorigenesis [ 4 ].

Therapeutically, HCC represents one of the most complex solid tumors to treat, with surgery and liver transplantation remaining the most effective treatment options [ 5 , 6 ]. Conventional chemotherapy is reserved for patients with the most advanced disease [ 5 , 7 ], and a particularly hostile tumor microenvironment makes it difficult for immunotherapy to achieve the intended results [ 8 , 9 ]. Therefore, the search for alternative, targeted therapeutic approaches is of the highest priority.

The aim of this review is to provide a comprehensive overview of the therapeutic targets for the treatment of HCC, from the best known to the emerging ones, focusing on both open issues and future perspectives ( Figure 1 ).

2. Targeted Therapy: State of the Art

2.1. General Standard of Care

The strategy for liver cancer therapy depends on many factors, including the histology, size of the lesion(s), their multiplicity, and stage of the disease. Comprehensive reviews about the main therapies adopted report surgical resection, liver transplantation, and loco-regional treatments as the main surgical and physical approaches [ 5 , 10 ]. Systemic chemotherapy is reserved for advanced HCC and includes doxorubicin, gemcitabine, and oxaliplatin [ 5 ]. The resulting overall survival is, however, still low, and alternative systemic therapies are under evaluation. Sorafenib (brand name: Nexavar®) and regorafenib (Stivarga®) are kinase inhibitors used to treat unresectable liver carcinoma ( https://go.drugbank.com , accessed on 25 January 2024). Sorafenib is a bi-aryl urea and an oral multikinase inhibitor. It targets cell surface tyrosine kinase receptors and downstream intracellular kinases that are implicated in tumor cell proliferation and tumor angiogenesis [ 11 ]. This mechanism of action is shared by regorafenib: in in vitro biochemical or cellular assays, regorafenib or its major human active metabolites, M-2 and M-5, inhibited the activities of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFRα, PDGFRβ, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically ( https://go.drugbank.com , accessed on 25 January 2024). In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model and inhibition of tumor growth, as well as anti-metastatic activity in several mouse xenograft models, including some for human colorectal carcinoma. Improvement in survival, though statistically significant, is, however, very limited with both drugs [ 5 , 12 , 13 , 14 , 15 , 16 ], which still imposes the need for better therapies.

2.2. Immunotherapy

Cancer cells are able to block immune cell activity by exposing on their surface the programmed cell death ligand (PDL-1, CD274) that interacts with receptors, called immune checkpoints, present on the surface of T-cells, like the B- and T-lymphocyte attenuator (BTLA), the programmed death protein 1 (PD-1), and the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) [ 17 ]. The resulting signals block T-cell-mediated immune responses to neoplasms and T-cell activation, allowing cancer cells to escape scrutiny and grow uncontrollably. Immune checkpoint inhibitors are drugs able to modify the tumor microenvironment, turning inactive immune cells into cells able to actively fight the tumor itself. There are currently six FDA-approved checkpoint inhibitor immunotherapies for liver cancer, for which the main features are summarized in Table 1 . All of them are antibodies. Two target PD-L1, atezolizumab (Tecentriq™) and durvalumab (Imfinzi™), two are anti-PD1 antibodies, pembrolizumab (Keytruda®) and nivolumab (Opdivo™), and two are anti-CTLA4 antibodies, ipilimumab (Yervoy™) and tremelimumab (Imjudo®). By interfering with the immune checkpoints, these molecules can remove the inhibition induced by the tumor from T-cells and allow the activation of the latter, unleashing their cytotoxic activity. Combinations of two immune checkpoint inhibitors are now known to enhance clinical responses, and the administration of atezolizumab along with bevacizumab has become the new standard of care for first-line unresectable HCC ( Table 1 ).

Although the field of classical, full-length monoclonal antibodies against HCC is thriving, alternative antibody-engineered solutions are still at the experimental stage and have had limited development. As further discussed in a following section, an anti-FGF2 diabody was found to inhibit the expression of PD-L1 and the epithelial mesenchymal transition (EMT) of hepatoma cells, suggesting a potential clinical application in inhibiting metastasis and immune escape [ 22 ], while a bispecific single-chain diabody targeting c-Met and PD-1 substantially decreased the tumor burden in an HCC model of high c-Met expression [ 23 ], which has led to the development of an analog, CAR-T [ 24 ].

2.3. Antibody–Drug Conjugates (ADCs)

Antibody–drug conjugates (ADCs) are complex molecules consisting of a targeting component, represented by an antibody or an engineered antibody fragment, joined to a toxic payload by a labile linker. The linker can be cleaved inside the cancer cells, after ADC internalization, typically at the level of the lysosomes. There are not yet ADCs approved for the treatment of HCC, though there is experimental work supporting their potential [ 25 ]. In this respect, two targets have been explored so far: the cell surface membrane-bound glypican-3 (GPC3), a heparan sulfate proteoglycan protein, and the cell membrane-bound CD24, which is a mucin-like molecule that is overexpressed in a range of human carcinomas, including HCC [ 26 ].

In the case of GPC3, two humanized mAbs (hYP7 and hYP9.1b) in the IgG format have been reported to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in GPC3-positive cancer cells [ 27 ]. Two ADCs composed of hYP7 coupled with duocarmycin or pyrrolobenzodiazepine dimer (PC) were able to kill cancer cells, with the latter being 5–10 times more potent than the former. In fact, a single treatment of hYP7-PC induced tumor regression in multiple mouse models [ 28 ].

By connecting a CD24-targeting antibody (G7mAb) to two doxorubicin molecules [ 29 ] or monomethyl auristatin E [ 30 ], the resulting ADCs were able to suppress tumor growth, decrease systemic toxicity, and prolong the survival of HCC-bearing nude mice.

Given the success of ADCs, like Adcetris™ (brentuximab vedotin), approved in 2011 for Hodgkin’s lymphoma, and Kadcyla™ (trastuzumab emtansine or T-DM1) approved for breast cancer in 2013, it is likely that this drug category might reserve positive surprises in the medium-long term in the treatment of HCC as well.

2.4. Chimeric Antigen Receptor T-Cells (CAR-Ts)

Following its success in hematology since its FDA approval in 2017 [ 31 ], cellular immunotherapy with chimeric antigen receptor T-cells (CAR-Ts) has been put to the test for several solid tumors, including HCC. A review of clinical trials relevant to the field was recently published [ 32 ]. T- and NK cells transduced with a CAR that recognizes the surface marker CD147 (basigin) could effectively kill various malignant HCC cell lines in vitro and HCC tumors in xenograft and patient-derived xenograft mouse models [ 33 ]. In fact, CD147 is over-expressed in several types of cancer, including HCC [ 34 , 35 ], and plays an important role in the tumor microenvironment’s (TME’s) regulation, particularly through the production of proteases involved in cell matrix degradation, which promotes cell invasion and metastasis [ 35 , 36 ].

CD133 is a marker that has long attracted interest as a potential therapeutic target, being expressed by cancer stem cells (CSCs). A Phase II study investigated CD133-directed CAR-T cells in adults with HCC, obtaining, out of 21 evaluable patients, 1 partial response, 14 stable diseases from 2 to 16.3 months, and 6 progressions [ 37 ].

CAR-Ts targeting GPCR3 were successful in suppressing tumor cell growth in HCC patient-derived xenografts [ 38 ]. GPC3 is a cell-membrane-anchored HSPG proteoglycan for which the overexpression in HCC cancer cells correlates with a poor prognosis [ 39 ] and that exerts its pro-tumoral function via the Wnt-signaling pathway [ 40 ]. A phase I trial established the initial safety profile along with early signs of the antitumor activity of GPC3-directed CART-s in patients with advanced HCC [ 41 ]. The potentiation of this effect was observed, including CD28, 4-1BB, or both, in two xenogeneic tumor models [ 42 ]. A clinical trial is currently underway to test the safety of a dual CAR-T directed against both CD147 and GPCR3 in patients with advanced HCC ( NCT03993743 ). CAR-T cells engineered to co-express IL-7 to induce proliferation and CCL19 to promote CAR-T migration to the tumor site have shown some of the most encouraging effects. The administration of this type of cells to patients with advanced GPC3+ HCC has yielded astonishing results in terms of intratumoral activity, with one patient having all the tumor cells eliminated 30 days after administration ( NCT03198546 ) [ 43 ].

An anti-alpha-fetoprotein (AFP) CAR-T has shown potent anti-tumor activity in vivo in mouse models [ 44 ], and a Phase I clinical trial has been conducted in patients with AFP+ HCC, the results of which are not yet available ( NCT03349255 ). Alpha-fetoprotein is, in fact, an established marker in HCC, being overexpressed in the vast majority of patients and being associated with drug resistance and increased tumor progression [ 45 , 46 ].

HBV-related advanced HCC has been treated with HBV-specific TCR expressed on T-cells, showing to be well tolerated, with most of the patients exhibiting a reduction in or stabilization of circulating HBsAg and HBV DNA levels [ 47 ]. Short sequences of integrated HBV-DNA present in HCC cells have also been found to encode epitopes that are recognized by and activate engineered T-cells, with initial clinical response [ 48 ].

Finally, NKG2DLs (NK group 2 member D ligands) are overexpressed in HCC cancer cells but absent in healthy ones [ 49 ], representing a promising target. In this sense, an example is MICA/B, an activating receptor that belongs to the class of NKG2DLs and is thus able to activate the cytotoxic effect of effector cells that express NKG2D, such as NK cells and CD8+ cells. The targeting of MICA/B has given promising results in vitro in patients with cholangiocarcinoma (CCA) [ 50 , 51 ].

NKG2D-expressing CAR-Ts were, therefore, designed to direct their action against tumor cells overexpressing NKG2DL, with good results obtained both in vitro and in vivo. NKG2D-based CAR-T cells comprising the extracellular domain of human NKG2D, 4-1BB, and CD3ζ-signaling domains (BBz) effectively eradicated SMMC-7721 HCC xenografts [ 49 ]. A clinical trial is underway to evaluate the safety of the administration of this CAR-T to patients with HCC ( NCT04550663 ).

CD155 is another emerging tumor target. Initially identified as a poliovirus receptor (PVR) [ 52 ], it is now known to be an immunoglobulin superfamily adhesion molecule involved in many different physiological processes ranging from cell adhesion and migration to the proliferation and modulation of immune responses [ 53 ]. It is also overexpressed in tumors, including HCC, interacts with the activating receptor DNAM-1 expressed on NK cells, and is involved in anti-tumor immune responses [ 54 ]. CD155 is also a high-affinity ligand of TIGIT [ 55 ], and interfering with the TIGIT-CD155 axis has shown promising results in enhancing CAR-T efficacy in experimental models [ 56 ].

3. Review of Established and Novel Potential Targets in HCC

HCC is acknowledged as a complex tumor, particularly in its tumorigenesis, stemming from a multi-step process involving adaptive genetic and epigenetic alterations [ 57 , 58 ]. In the last decade, efforts to better understand the cancer biology of this challenging tumor have revealed recurrent alterations in foundational signaling pathways within cell biology, such as tyrosine receptor pathways, RAS/MAPK, JAK/STAT, PIK3/AKT/mTOR, WNT/β-catenin, and cell cycle regulation [ 59 , 60 , 61 , 62 , 63 ]. This ignited the search for suitable targets for targeted therapy, which has proven to be, and remains, particularly challenging, as these pathways are broadly active in most cells. However, a progressively deeper understanding of the individual actors causing such altered regulation has provided a more specific focus on molecular and cellular components that could result in effective targets. In the following section of this review, we report the results of a survey performed through an extensive literature search ( Table 2 and Table 3 ). Of particular interest in this regard is the proteomic work performed in [ 64 ], which also revealed as-of-yet unclassified molecules potentially useful as therapeutic targets.

Given the broad nature of the topic covered, the following discussion has been structured first to cover the receptors and ligands primarily involved in the altered signaling found in HCC and then to focus on the major affected pathways.

The hope is that this work will provide a fresh look at the best-known targets of HCC and new perspectives for the search for novel therapeutic targets.

3.1. Receptor Tyrosine Kinases (RTKs)

Alterations in the signaling pathways mediated by growth factors (GFs) and receptor tyrosine kinases (RTKs) are known to have a leading role in oncogenesis. GFs are polypeptides carrying mitogenic messages and are considered as mediators of paracrine cellular communication, acting mostly on cells located near the one that secreted them. With more than 100 GFs and 58 RTKs grouped in 20 families, these pathways are involved in the regulation of numerous and variable cellular processes [ 65 ]. All the RTKs are activated through a unique mechanism, consisting of dimerization followed by the autophosphorylation of tyrosine residues located near the C-terminal of the intracellular domain. These phosphotyrosine residues can be recognized by proteins carrying the so-called SH2 (SRC homology domain 2) and PTB (phosphotyrosine-binding domain) domains, which can implement the signal either by being phosphorylated (e.g., JAK) or by being recruited as docking proteins, starting the formation of protein complexes, which then initiate larger signaling cascades (e.g., RAS/MAPK and PI3K pathways).

RTK signaling is known to be severely altered in HCC [ 58 ], and, along with their soluble ligands, RTKs have a crucial role in redirecting the crosstalk occurring in the TME toward pro-tumoral functions.

In the following section, we will briefly discuss the main classes of RTKs, along with their ligands, involved in oncogenesis and the progression of HCC and their potential as therapeutic targets.

3.1.1. Epidermal Growth Factor Receptors (EGFRs)

The erythroblastic leukemia viral oncogene homolog (ErBb) family consists of the epidermal growth factor receptors, EGFRs, also called ERBB1 or HER1, ERBB2, ERBB3, and ERBB4, and plays a pivotal role in the progression of various cancers. These receptors are implicated in the regulation of fundamental cellular processes, including proliferation, regeneration, survival, migration, angiogenesis, tumorigenesis, and metastasis [ 66 ].

Within this family, the class I EGFR is a transmembrane receptor composed of an extracellular domain to which ligands bind, followed by a transmembrane domain and an intracellular domain, where the tyrosine kinase domain and the carboxy-terminal tail containing key tyrosine residues are located [ 67 , 68 ]. Upon ligand binding, homo- or heterodimers are formed with the related receptors, ERBB2, ERBB3, and ERBB4, and kinase activation initiates multiple intracellular signaling pathways.

EGFR can be activated by several ligands, like the epidermal growth factor (EGF), the transforming growth factor α (TGFα), amphiregulin (AR), epiregulin (EREG), betacellulin (BTC), heparin-binding EGF (HB-EGF), and epigen (EPGN) [ 69 , 70 ]. The subsequent signaling events have been summarized in several classical reviews [ 68 , 71 ].

Studies have revealed a significant association between EGFR and liver cancer. EGFR is overexpressed in human cirrhotic liver tissue and in 66% of human HCCs, correlating with aggressive tumors, metastasis, and poor patient survival [ 72 ]. Aberrant EGFR activation through gene amplification and/or mutation, though common in various types of cancer, is not frequently found in HCC [ 66 ]. Notably, EGFR is detected in endothelial cells within cancerous tissue but is absent in healthy liver tissue, hinting at a potential avenue for therapeutic selectivity [ 73 ].

EGFR is expressed in liver macrophages both in human HCC and mouse HCC models, being critical for HCC development, as demonstrated by specific deletion in KCs/macrophages [ 74 ]. This points to the role of EGFR in the interaction between the components of the TME. Recently, it has also been shown that EGF/EGFR can mediate EMT through the AKT/glycogen synthase kinase-3β (GSK-3β)/snail signaling pathway to promote HepG2 cell proliferation and migration [ 75 ]. The pharmacological or genetic inhibition of EGFR in different models of hepatic injury ending in HCC prevents tumor development [ 76 , 77 , 78 ].

Because of all these observations, EGFR represents, in principle, a rational target for anti-tumor strategies. However previous attempts with anti-EGFR agents have shown no effective response in HCC patients [ 79 , 80 ]. These observations are ascribed to increasing evidence of EGRF acting as a “signaling hub” where different extracellular growth and survival signals converge [ 81 ] thanks to transactivation, the process whereby a primary agonist, via binding to its receptor, activates a receptor for another ligand. This situation can typically occur with G-protein-coupled receptors (GPCRs), leading to the activation of growth factor receptors. For example, the binding of an agonist to a GPCR in primary cells leads to the release of epidermal growth factor (EGF), which in turn activates EGFR [ 82 ].

Both ligand-dependent and ligand-independent transactivations of EGFR have been described [ 81 ], pointing to the high complexity of this signaling system.

Even regulators of EGFR signaling have been described as altered, e.g., ERBB receptor feedback inhibitor 1 (ERRFI1), which is deleted in HCC [ 83 ].

Another protein of interest interacting with EGFR is the urokinase-type plasminogen activator receptor (uPAR). Many studies have shown increased levels of the urokinase-type plasminogen activator receptor (uPAR) in HCC, which are related to liver metastasis and a poor prognosis [ 84 , 85 , 86 , 87 ]. The urokinase-type plasminogen activator is a key protein in the plasminogen activation system, which plays a proteolytically important role in the invasion and metastasis of various cancer cells. Attempts to target it in other cancer types is leading to interesting results, even in the surgical domain [ 88 ], and it is, therefore, not surprising that it has now become the focus of interest for integrated antitumor therapeutic strategies [ 87 ].

In addition to EGFR, ligands, such as TGFα, EGF, HB-EGF, AR, and BTC, along with ADAM17, show heightened expressions in human liver tumor cells and tissues [ 70 ]. EGFR ligands are also overexpressed in chronic liver injury, as shown both in experimental models and human cirrhotic tissue [ 89 ]. This may favor the hepatocarcinogenic process.

TGFα, a cytokine known for its mitogenic effect on hepatocytes, has been implicated in promoting liver carcinogenesis [ 90 ]. Intriguingly, it was suggested that the upregulations of TGFα and EGFR in hepatocytes, particularly in cirrhotic hepatocytes, are induced by a state of hypoxia, supporting their therapeutic potential in liver cancer [ 91 ]. The role of EGF, however, remains less clear in HCC progression. Evidence suggests its involvement in creating an autocrine loop leading to increased expression of TGFβ, thereby favoring HCC progression [ 92 ]. This intricate interplay of ligands and receptors underscores the complexity of the molecular landscape in liver cancer.

Beyond EGFR, recent findings highlight the overexpressions of ERBB2 and ERBB3 in different tumor cohorts [ 93 ]. ERBB3, in particular, has been linked to lapatinib sensitivity induced by the HBV-X protein [ 94 ].

The ERBB family members (ERBB2, ERBB3, and ERBB4) are also the dominant receptors for neuregulin 1 (NRG1), which has been identified as a positive regulator of the HCC EMT and metastasis [ 95 ]. This further underscores the multi-faceted role of ERBB receptors in shaping the aggressive phenotype of HCC.

3.1.2. Platelet-Derived Growth Factor Receptors (PDGFRs)

Platelet-derived growth factor receptors (PDGFRs) are class III tyrosine kinase receptors localized in the plasma membrane in the form of α or β monomers. PDGFs and their ligands are divided into four classes (A, B, C, and D), which can pair to form five different dimeric configurations (AA, AB, BB, CC, and DD) [ 96 , 97 , 98 , 99 , 100 , 101 , 102 ].

Binding to the respective ligands leads to the formation of dimers that can be composed of PDGFR-αα, -αβ, and -ββ. PDGFRα and PDGFRβ share different ligands and downstream effectors, and their distinct functions at a regulatory level in different cell types are mainly due to differences in spatial–temporal expression patterns [ 103 ]. PDGFs are mainly released by endothelial and epithelial cells, macrophages, and platelets after degranulation [ 104 ].

The PDGF/PDGFR axis is implicated in the regulation of several signaling pathways involved in cell growth and differentiation, particularly of mesenchymal stem cells [ 105 ]. Major ones include the RAS/MAPK, PI3K-AKT, and PLC gamma pathways [ 106 ].

The altered expression levels and upregulation of the PDGF/PDGFR-signaling axis have been found in several types of cancer [ 104 , 107 ]. These can occur at the level of the tumor cells themselves through autocrine signaling [ 108 ] or at the level of non-tumor cells in the TME [ 109 , 110 ]. In the liver, PDGFs are important proliferative agents, particularly for hepatic stellate cells (HSCs), which are an important cellular component in liver fibrosis and cirrhosis [ 111 , 112 ], as well as in the TME of HCC. Here, HSCs play an important role in facilitating tumor progression by actively contributing to the processes of angiogenesis, acquisition of invasive capabilities, and metastasis [ 113 ], as well as in promoting an immunosuppressive environment through the induction of T-regs (regulatory T-cells) and MDSCs (myeloid-derived suppressor cells) [ 114 , 115 ].

It was previously demonstrated that PDGFRα overexpression in HCC is a prognostic marker [ 116 ], while PDGFRB showed the highest overexpression rates among the potential HCC drug targets [ 93 ]. However, the role of PDGFRs in HCC remains complex, with research suggesting its involvement in various aspects of the disease.

In particular, the role of PDGFRα in HCC carcinogenesis appears to be of increasing importance. There is growing evidence linking altered PDGFRα-mediated signaling with increased tumor progression and metastasis [ 117 , 118 ]. In particular, this would be due to not only its critical role in promoting angiogenesis during HCC development but also its subsequent metastatic progression [ 119 , 120 ].

In addition, the strong involvement of the PDGFA/PDGFRα axis in promoting the epithelial–mesenchymal transition (EMT) of HCC, as confirmed by several in vivo studies [ 121 , 122 , 123 , 124 ], further supports the correlation between its altered signaling and tumor metastatic capacity. A more detailed analysis of the mechanisms by which PDGFRα is involved in promoting tumor progression in HCC can be found in the comprehensive review by Kikuchi et al. [ 125 ].

Targeting strategies for the PDGF/PDGFR axis essentially involve the use of neutralizing antibodies directed against the receptor/ligand or small-molecule inhibitors [ 104 ]. There are currently no reports regarding the development of CAR-T directed against these receptors. To date, only one monoclonal antibody directed against PDGFRα is approved for the treatment of tissue sarcoma (olaratumab), while a large number of small-molecule inhibitors directed against PDGRFα are used for the treatment of several cancers, including sunitinib (renal cell carcinoma), imatinib (leukemias and myelodysplastic/myeloproliferative disease), ripretinib (gastrointestinal stromal tumors), and erdafitinib (urothelial carcinoma) ( https://go.drugbank.com , accessed on 25 January 2024). In HCC in particular, the importance for targeting these receptors is demonstrated by the fact that sorafenib and regorafenib, among the main first-line drugs in the treatment of unresectable HCC, are multi-tyrosine kinase inhibitors that, among others, precisely act against PDGFRs [ 12 , 126 ].

3.1.3. Fibroblast Growth Factor Receptors (FGFRs)

As for class IV receptors, an alteration in the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling axis, which regulates cell proliferation, differentiation, and survival, is observed in multiple cancers, including HCC [ 127 ]. In fact, the levels of at least one FGF8 subfamily member and/or one FGFR are upregulated in 82% of HCC cases [ 128 ].

On the receptor side, FGFR3 and FGFR4 are the major FGFRs overexpressed in HCC, while the upregulations of FGFR1 and FGFR2 are rarely observed. FGFR3 isoforms have already been proposed as novel therapeutic targets years ago [ 129 , 130 ]. FGFR4 has recently been identified as an oncogenic-driver pathway for HCC patients [ 131 ], as also confirmed by proteomic analysis [ 93 ].

Regarding the soluble ligands, FGF2, which is barely detected in nonparenchymal cells or noncancerous liver tissue, is overexpressed in HCC, like FGF8, FGF17, and FGF18. Moreover, FGF19 plays a crucial role in liver carcinogenesis and progression.

Components of the FGF1 subfamily act through autocrine signaling and have long been implicated in promoting proliferation, invasiveness, and angiogenesis in HCC. Notably, FGF1 and FGF2 are expressed in the presence of chronic disease in the liver, and their elevated expression levels correlate with more advanced tumor stages [ 132 , 133 , 134 , 135 ]. Of the FGFs, FGF2 has been the most extensively studied, and FGFR3 appears to be most involved in HCC progression [ 136 , 137 , 138 ]. As previously discussed, an anti-FGF2 diabody could represent a potential therapeutic agent for the inhibition of metastasis formation and immune escape because it was able to inhibit the anti-PD-L1 expression and EMT in hepatoma cells [ 22 ].

In the FGF8 subfamily, FGF8, FGF17, and FGF18 components bind to FGFR2, FGFR3, and FGFR4 receptors, respectively. They act as mediators of paracrine signaling and have been found to be actively involved in the promotion of polypharylation, malignancy, and angiogenesis in HCC [ 128 ]. Notably, FGF8 is involved in conferring resistance to the EGFR inhibitors [ 139 ].

On the other hand, the FGF19–GFR4–KLB signaling pathway is recognized as a major driver of disease initiation and progression, being involved in the regulation of cell proliferation, survival, EMT, migration, and invasion in HCC cells [ 132 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 ].

Components of the FGF19 subfamily act as endocrine hormones, of which FGF19 is the main representative involved in liver cancer.

FGF19 does not appear to be expressed in the liver under physiological conditions, whereas its elevated presence has been reported in several liver diseases (hepatitis C, cirrhosis, and HCC) [ 132 , 148 ]. The overexpression of FGF19 at the protein level in HCC tissues is also closely correlated with larger tumor sizes, advanced disease stages, and early recurrence [ 132 , 149 , 150 ].

Given the important role of this receptor family in the development and progression of HCC, several inhibitors of the FGF/FGFR signaling pathway have been developed over the years, from the early multi-target pan-FGFR to the more recent selective FGFR4 inhibitors currently in Phase I/II clinical trials ( NCT04194801 and NCT02508467 , respectively).

3.1.4. Vascular Endothelial Growth Factor Receptors (VEGFRs)

Vascular endothelial growth factors (VEGFs—VEGFA, VEGFB, VEGFD, VEGFE, and PIGF) are an important class of growth factors playing a critical role in the regulation of angiogenesis and vascular permeability through interaction with their receptor VEGFRs (VEGFR1, VEGFR2, VEGFR3, and class V RTKs) [ 151 ]. Specifically, VEGFR1 is more characteristic under pathological conditions, including inflammation and cancer, whereas VEGFR2 signaling appears to be more focused on the regulation of vascular endothelial cell proliferation and permeabilization, as well as survival signaling pathways [ 151 , 152 ]. The regulation of many factors involved in this signaling axis is mediated by the hypoxia-inducible factor (HIF) [ 153 , 154 ].

The canonical VEGF-R1/R2-mediated signaling pathway results in the activation of several kinases that are involved in important pathways regulating cell proliferation, migration, and spreading, as well as angiogenesis and vascular permeability, as mentioned above [ 152 ]. Among the major ones, there are PLC-γ, PI3K, AKT, RAS, SRC, and MAPK [ 155 ].

The implication of the VEGF/VEGFRs axis in the development and progression of several solid tumors has long been recognized [ 156 , 157 ]. The overexpressions of VEGFs/VEGFRs by stromal cells present in the TME induce angiogenesis by stimulating endothelial cell proliferation and increased vascular permeability [ 158 , 159 , 160 ]. However, VEGFs/VEGFRs are found to be also overexpressed in cancer cells, suggesting autocrine or paracrine signaling that directly stimulates the growth of the cancer cells themselves [ 156 , 161 ].

There is evidence that the VEGF/VEGFR autocrine signal axis is present in HCC cancer cells, with the overexpression of both promoting their growth and progression [ 157 , 162 , 163 , 164 , 165 ]. Recently, a large set of virus-associated liver cancers was classified according to proteomic profiling, whole-genome sequencing, and transcriptional analysis [ 64 ]. Among the three proteomic subclasses defined (R1, R2, and R3), the R2 subclass contains advanced proliferative tumors with TP53 mutations, high expression of VEGF receptor 2, and the worst prognosis but also four known targets of multikinase inhibitors: VEGFR2, CRAF, BRAF, and c-Kit, where c-Kit represents an as-of-yet underexplored target. VEGFR2 was overexpressed in HCC classified as R2 (the most aggressive cancer type) in [ 64 ], while VEGFR1-HIF1A was found to be selectively upregulated in the R3 proteomic class. The latter class corresponded to smaller and less aggressive tumors enriched with CTNNB1 mutations and possessing elevated mTOR-signaling-pathway activity.

From a clinical point of view, the high expression of VEGF in the tumor tissue and serum of patients with HCC correlates closely with the metastatic stage of the tumor as well as its size [ 166 , 167 , 168 ]. All these data confirm the therapeutic relevance of this family of targets.

Several of the small-molecule multi-tyrosine kinase inhibitors previously discussed for PDGFRs also act on VEGFRs (e.g., sunitinib), and, in particular, sorafenib and regorafenib, for which their use is well established in HCC therapy. In addition, several antibodies directed against VEGF/VEGFRs have been developed for the treatment of HCC. The first to be approved for the treatment of many solid tumors was bevacizumab, an anti-VEGF ligand antibody, which is currently being investigated for its therapeutic efficacy in HCC in several Phase III clinical trials, particularly in combination with atezolizumab ( NCT04487067 , NCT04732286 , NCT04102098 , NCT03434379 , and NCT05904886 ). Ramucirumab is an anti-VEGFR2 antibody that is being evaluated in Phase III clinical trials ( NCT02435433 and NCT01140347 ), with positive results in terms of increasing the overall survival (OS) and progression-free survival (PFS). In recent years, many efforts have been made to develop CAR-Ts targeting the VEGFR family of receptors. At present, none has reached the stage of clinical development, but in both in vitro and in vivo experiments, it has been observed that the use of CAR-T cells targeting VEGFR1, VEGFR2, and VEGFR3 positively prolonged the survival of mice and inhibited the growth of several types of solid tumors [ 169 , 170 , 171 , 172 ], although none of these studies has been performed in HCC so far. A detailed review on this topic can be found in [ 173 ].

3.1.5. Mesenchymal–Epithelial Transition Factor (c-Met)

Hepatocyte growth factor (HGF) is a growth factor that was initially identified for its mitogenic properties toward hepatocytes [ 174 , 175 , 176 ] and that, over the years, has been shown to have a complex role in the regulation of liver functions, in particular, in cell motility, angiogenesis, immune responses, cell differentiation, and anti-apoptotic effects [ 177 ]. In HCC, it is known that both stromal and tumor cells release HGF in the TME, which affects tumor cells through autocrine and paracrine signaling by binding to their c-Met receptors [ 162 ].

c-Met belongs to the tyrosine kinase receptor family and interacts with its high-affinity ligand, HGF, through four regions called hotspots [ 178 ]. We refer to HGF-mediated c-Met activation as the canonical pathway, which, through homodimerization, induces signaling pathways, such as RAS/MAPK, ERK, PI3K, p38, and AKT/PKB [ 179 , 180 ].

However, c-Met can also be activated through the so-called non-canonical pathways, which are mostly associated with tumor progression, metastasis, and drug resistance [ 174 , 177 , 181 ]. Some of the most important include activation by des-gamma carboxy prothrombin (DCP), which is highly secreted by HCC cells [ 182 ]; interaction with other receptors, such as EGFR, integrin, beta-catenin, CD44, MUC1, and FAK [ 177 , 183 , 184 ]; hypoxia and miRNA loss [ 185 ]; and receptor-activating mutations and amplification [ 177 ].

The role of c-Met in liver disease is dual, as its overexpression is generally necessary to activate hepatocyte proliferation and liver regeneration in case of injury and to slow the progression of injury by suppressing chronic inflammation and fibrosis progression. At the same time, however, its overexpression has been shown to be involved in promoting the initial development and later progression of HCC [ 186 ].

Although not all cases of HCC are characterized by c-Met overexpression, where it is found, it correlates with a worse prognosis [ 187 ]. In contrast, HGF expression is found to be decreased in HCC tissue, whereas it is increased in peritumoral tissue [ 177 ]. Nevertheless, several studies correlate the high activity of this axis with the invasiveness and metastatic capacity of HCC [ 188 ], with an important role played by the TME, where high levels of HGF secreted by neutrophils, mesenchymal cells, and CAFs appear to be critical for the acquisition of these invasive features [ 189 , 190 , 191 ].

Attempts have also been made to use HGF levels in the serum of HCC patients as a diagnostic tool, which resulted, however, in being inadequate when considered as a single indicator [ 192 , 193 ]. In fact, the difference between the serum HGF levels of patients with cirrhosis and patients with both cirrhosis and HCC was not significant, but with a diagnostic sensitivity of 90.62%, the potential of this indicator is evident [ 193 ].

It is, therefore, well established that the HGF/c-Met axis represents a valuable therapeutic target in HCC, with increasing evidence both in vitro and in vivo [ 194 , 195 , 196 ]. Over time, the need to focus on the interaction of c-Met and downstream signaling mediators rather than the classical HGF/c-Met interaction is becoming more and more evident, given the greater involvement of non-canonical activation pathways in the c-Met signaling pathway.

Currently, 10 inhibitors of c-Met have been tested in clinical trials [ 186 ], belonging to three macro categories: selective c-Met tyrosine kinase inhibitors (TKIs); multi-targeted TKIs, including c-Met; and monoclonal antibodies against HGF and c-Met [ 197 ]. However, no effective treatment for HCC based on traditional TKI monotherapy has been found. Particularly promising was tivantinib, a highly selective c-Met inhibitor, which was able to increase the median time to progression and OS in a Phase II study [ 198 ]. Unfortunately, the subsequent randomized Phase III trial showed no significant OS increase in patients with advanced HCC and high c-Met expression treated with sorafenib compared to a placebo ( NCT01755767 ), compromising the possibility of further development for clinical use.

Other c-Met inhibitors are being evaluated in clinical trials for the treatment of HCC. These include the non-selective TKI inhibitor cabozantinib in Phase III ( NCT01908426 ), which increased OS from 8 to 10.2 months compared to a placebo and is currently being evaluated in combination with atezolizumab versus sorafenib in another Phase III trial ( NCT03755791 ). Among the selective inhibitors, tepotinib showed promising results in a Phase II trial versus sorafenib ( NCT01988493 ), and capmatinib is being tested in Phase II trials ( NCT01737827 ).

The major issues detected in early clinical trials with c-Met inhibitors are mainly related to severe side effects. A possible solution to this problem would be to target downstream effectors, among which several have been proposed, including the Grb SH2 domain, Src, MAPK, STAT3, and Shp2 [ 199 ], some of which are also discussed in this work. However, their involvement in pathways regulated by numerous other RTKs makes them risky to target, as the results of such treatments would be difficult to predict. Therefore, the identification of downstream effectors in the c-Met pathway that may be more specific remains an open question.

It is also important to mention the use of miRNAs as an alternative to inhibitors for c-Met targeting. This therapeutic approach would be based on non-coding RNA molecules that can regulate protein expression by suppressing mRNA translation [ 200 ], which is proving to be increasingly promising in preclinical studies [ 201 , 202 , 203 , 204 , 205 ]. In the clinic, however, the current studies are mainly evaluating the potential role of circulating miRNAs for diagnostic and prognostic purposes ( NCT02928627 , NCT05148572 , and NCT02448056 ).

Concerning other promising therapeutic approaches, good results have been obtained by testing CAR-T directed against c-Met in different types of solid tumors, such as renal, gastric, and breast cancers [ 206 , 207 , 208 , 209 ]. In HCC, the best results were obtained with a dual CAR-T directed against both c-Met and PD-1, which showed a good improvement in anti-tumor activity along with the increased persistence of CAR-T cells after administration ( NCT03672305 ) [ 24 ].

All in all, despite the complexities encountered in the development of effective targeting strategies for the HGF/c-Met axis, its therapeutic potential has been extensively demonstrated, confirming the need for further efforts to effectively target this important pathway.

3.2. Toll-Like Receptors

Toll-like receptors (TLRs) are a family of transmembrane receptors involved in innate immunity and located in the plasma membrane (TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10) or in the endosomal membranes (TLR3, TLR7, TLR8, and TLR9). Their activation occurs through dimerization commonly induced by the recognition of PAMPs (pathogen-associated molecular patterns) or DAMPs (damage-associated molecular patterns) released owing to infection, tissue damage, or necrosis.

Several studies confirm that alterations in TLR signaling have a significant impact on HCC development and progression. Recently, a TLR-based gene signature able to act as a robust prognostic indicator in HCC was identified, further confirming their pivotal role [ 210 ]. In particular, TLR2 and TLR4 are known to orchestrate the so-called hepatic inflammation–fibrosis–carcinoma sequence (IFC), which frequently leads to HCC onset [ 211 ]. In fact, TLR2 and TLR4 activations trigger the signaling of NF-kβ and MAPK, which eventually leads to the release of several inflammatory mediators, such as TNFα and cyclooxygenase 2 (COX-2) [ 212 , 213 , 214 , 215 ].

TLR2 is found to be functionally expressed on the cell surface of almost all types of liver cells, including hepatocytes [ 216 ] and Kupffer, stellate, and sinusoidal endothelial cells [ 217 ]. Its role in the promotion of chronic liver disease progression is well assessed [ 218 ], while growing evidence in recent years has also been elucidating its involvement in the promotion of HCC development, making it a promising therapeutic target [ 219 , 220 ]. It has been shown in vitro and in vivo that the knockdown of TLR2 could inhibit cultured-HCC growth and proliferation [ 220 ]. It has also been demonstrated that TLR2 has an impact on HCV viral loads, leading to higher risk of HCC onset in HCV-infected patients [ 221 ]. Recently, a correlation between the expression of TLR2 and other markers of malignancy in HCC has been established, in particular with proliferation, apoptosis, and vascularization HCC markers (Ki-67, Caspase 3, and VEGF, respectively) [ 222 ]. For the first time, a vaccine based on a TLR2 ligand is being tested in combination with atezolizumab for the treatment of HCC in a Phase I clinical trial ( NCT05937295 ).

TLR4 has also been intensively studied for its role in carcinogenesis, metastasis, and cancer progression [ 223 , 224 ]. In the liver, TLR4 is normally expressed on the cell surface of hepatocytes, Kupffer cells, and hepatic stellate cells but at relatively low levels. However, in the presence of liver damage, TLR4 expression is upregulated [ 225 ]. Growing evidence supports TLR4’s crucial role in the so-called liver inflammation–fibrosis–carcinoma (IFC) sequence, modulating the inflammatory response in viral hepatitis, autoimmune liver disease, and alcohol-induced liver damage. It is well documented that TLR4 expression is increased in livers with viral hepatitis [ 211 ], and its concurrent overexpression with TLR9 was correlated with a poor prognosis in HCC patients [ 226 ].

TLR4 activation, mainly mediated by DMAPs and lipopolysaccharide (LPS), its major agonist, leads to the upregulation of the NF-kβ and MAPK pathways, resulting in the secretion of pro-inflammatory mediators, such as TNFα and IL-6 [ 211 ]. The stimulated immune response plays an important role in sustaining DNA damage and supporting genomic instability that eventually leads to hepatocyte neoplastic transformation, leading to HCC development [ 227 ]. In recent years, growing evidence has suggested a more complex role for TLR4 in HCC progression, with several aspects to be considered in metastasis promotion, drug resistance, and angiogenesis support [ 228 ]. There is evidence, in HCC, of TRL4 involvement in the facilitated recruitment of T-regs to the tumor site, along with metastasis promotion through its interaction with macrophages [ 229 ]. In particular, a deviation from the canonical LPS-induced TLR4/myD88 activation and M1 polarization seems to be caused specifically by its ability to recognize distinct HCC necrotic debris, resulting in increased metastatic potential [ 230 ]. TLR4’s higher expression in relapsing hepatocellular carcinoma patients has recently been linked to its newly discovered regulatory role in the enhancement of stem properties in HCC cells via the TLR4–AKT–SOX2 pathway [ 231 ]. It has also been demonstrated that TLR4 contributes to the regulation of VEGF by LPS-activated STAT3/SP1 signaling, promoting angiogenesis [ 232 ]. To date, no clinical trial targeting TLR4 in HCC is ongoing, while the TLR4 agonist GLA-SE has been tested for the treatment of advanced soft-tissue sarcoma ( NCT02180698 , Phase I) and stage II-IV melanoma ( NCT02320305 , Early Phase I).

3.3. Chemokine Receptors

Chemokines are a family of small protein molecules (~10 kDa) similar in structure, function, and chemotactic properties and are divided into four subclasses: CX 3 C, CXC, CC, and XC, according to the arrangement of the two conserved cysteine residues found at their N-termini. Their receptors are grouped according to the same scheme and belong to the G-protein-coupled receptor (GPCR) family, a group of surface receptors characterized by the presence of a 7-fold transmembrane domain [ 233 ].

Chemokines are known to play a pivotal role in the immune system by being the major mediators of the chemotactic effect and by directly influencing the differentiation, survival, and function of immune cells [ 234 , 235 , 236 ].

It has been reported that the chemokine system has wide-ranging effects in hepatocellular carcinoma (HCC) by influencing immune and tumor microenvironment (TME) cells, leading to both anti- and pro-tumoral outcomes. As discussed below, the presence of chemokine receptors on HCC cells enables the direct modulation of the tumor cell behavior, affecting processes such as migration, proliferation, growth, and survival. Recently, a prognostic chemokine-receptor-based signature was successfully established (CCL14–CCL20/CCR3) [ 237 ], further confirming them as fertile ground to look into for finding potential therapeutic targets.

The classes of chemokine receptors mostly involved in HCC are CXCRs and CCRs.

The role of CXCL12/CXCR4–CXCR7 is well-documented, with abnormal expression levels of either CXCL12 or CXCR4/CXCR7 correlating with clinicopathological features of HCC [ 238 , 239 , 240 , 241 ]. The level of CXCR4 expression in HCC tissues correlates with tumor size, metastasis, and survival [ 242 ], and CXCL12/CXCR4 plays an important role in the epithelial–mesenchymal transition, with TGFβ-induced EMT correlating with high CXCR4 expression in tumor tissues, particularly corresponding to tumor borders and perivascular areas [ 243 ]. Besides TGFβ, other molecules present in the TME, such as osteopontin and astrocyte-elevated-gene-1, significantly upregulated the expression of CXCR4 in HCC [ 244 , 245 ]. The CXCL12/CXCR4 axis is also known to increase hypoxia-inducible factors and activate MMPs, providing another way to promote angiogenesis and cancer metastasis simultaneously [ 246 ]. All in all, CXCR4 seems to be a valuable target in HCC, and with its agonist Mozobil™ (AMD3100) already approved by the FDA [ 247 ], there is a solid possibility that its testing in HCC combined therapy will happen soon.

Other important chemokine axes are worth mentioning though. For instance, CXCL9–CXCL10/CXCR3, which has prognostic value in HCC patients [ 248 ], along with CXCL1–CXCL2/CXCR2, for which upregulation is an indicator of increased risk for HCC development [ 249 ]. The CXCL5/CXCR2 axis activates the PI3K/AKT/GSK-3/snail signaling pathway, inducing EMT in HCC cells and significantly enhancing the invasive and migratory properties of HCC cells [ 250 ]. Finally, high levels of CXCR6 found in HCC tissues result in increased expressions of IL-6 and IL-8 and correlate with higher neutrophil infiltration and worse prognoses for HCC patients, through the generation and maintenance of an inflammatory environment and promotion of tumor invasiveness [ 251 ].

In the second subclass of interest, several receptors need to be considered. Expression levels and genetic alterations of CCL2/CCR2 affect HCC patients’ prognoses [ 252 ], with CCL2 promoting angiogenesis initiation and HCC progression. This is accompanied by increased invasiveness and EMT, along with the activation of the Hedgehog pathway [ 253 ].

The CCL5/CCR5 axis is tightly connected to chronic liver inflammation and actively linked to HCC development [ 254 ]. The expression of both CCL5 and CCR5 in HCC tissues is significantly higher than in healthy liver tissues, and the CCR5 antagonist maraviroc can reverse the CCL5-mediated activation of the PI3K/AKT/mTOR pathway, inhibiting HCC progression in vivo [ 255 ]. Also, CCR10 was found to be significantly upregulated in inflammation-driven HCC tumors and in hepatocytes of paracancerous tissue, where it is secreted, activating PI3K/AKT signaling, inhibiting apoptosis, and promoting cell proliferation, leading to HCC onset [ 256 ]. Finally, CCL20/CCR6 promotes the adhesion, proliferation, and chemotactic migration of HCC cells [ 257 ]. There is evidence that blocking CCR6 activity in the tumor microenvironment inhibits tumor neovascularization and, therefore, might enhance traditional therapy’s effectiveness [ 258 ].

3.4. RAS/MAPK Pathway

The mitogen-activated protein kinase (MAPK) pathway is responsible for coordinating different cell functions, like cell proliferation, metabolism, migration, and differentiation, and responding to apoptosis. Its signaling cascade is extremely complex, and growth factors and mitogens use it to transmit signals from their receptors to regulate gene expression and prevent apoptosis [ 259 ]. Given its central role in controlling cell functions, the dysregulation of the MAPK pathway is associated with tumorigenesis, cancer progression, and drug resistance [ 260 ]. The pathway is triggered by the activation of proteins belonging to the RAF family (ARAF, BRAF, and CRAF), which are serine/threonine kinases that act as mediators between the upstream proteins, RAS/GTPases, and downstream kinases, such as MEK/ERK, c-Jun NH2-terminal kinase (JNK), and p38. Extracellular signaling mediated by receptors or physical stressors can activate the MAPK pathway physiologically [ 261 ]. The aberrant activation of the pathway can depend on the dysregulated activation of signal receptors (discussed previously in this review) or of upstream and downstream kinases involving mainly the MEK/ERK signal transduction pathway [ 262 ]. In cancer, the upstream RAS proteins are the proteins that are the most frequently mutated, and the RAS mutational and activation burdens can predict the prognosis, drug sensitivity, and survival. Mutations in NRAS, KRAS, and HRAS are found in 20% of cancers, with KRAS being the most frequently mutated protein (15%). RAF proteins, which are RAS upstream effectors, are also mutated in 20% of cancers, with BRAF and ARAF being the most frequently mutated (10% and 8%, respectively). Cancers have lower rates of mutations in MEK protein kinases, which are downstream mediators of RAS/RAF signaling (MAK1 2%, MAK2 5%, and ERK 3%) [ 263 , 264 ].

In HCC, the dysregulated activation of the MAPK pathway is the most frequently related to aberrant upstream signaling rather than gain-of-function mutations in RAS/RAF/MEK proteins. The mutational frequency of RAS proteins in HCC is 4%; in pancreatic cancer, it is 90%; and in colorectal cancer, it is 62%. However, the RAS/MAPK pathway is activated in 50–100% of human HCCs and is correlated with a poor prognosis [ 265 , 266 ]. CRAF and BRAF activation were confirmed to be altered in HCC [ 64 , 267 ], and CRAF overexpression is considered as a marker of poor prognosis in HCC [ 265 , 268 ].

Few drugs targeting MAPK pathways have been approved by the FDA and EMA, even though many molecules are being tested in preclinical models. In HCC, the MEK1 inhibitor selumetinib has already been tested without success in a Phase I clinical trial in patients with advanced cancer [ 269 ]. A similar outcome has been reported for the MEK1 and MEK2 inhibitor trametinib, which has been tested in combination with sorafenib in patients with advanced HCC ( NCT02292173 ) [ 270 ].

3.5. JAK/STAT Pathway

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is activated by various cytokines and growth factors. In humans, four members of the JAK family (e.g., JAK1, JAK2, JAK3, and TYK2) and seven members of the STAT family (e.g., STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6) have been described to date [ 271 ]. The activation of JAK/STAT signaling involves receptor-associated JAK activation after ligand–receptor binding, leading to the recruitment of STAT proteins to the receptor’s cytosolic domain. Phosphorylation by JAK activates STAT proteins, allowing them to form dimers, migrate into the nucleus, and bind to DNA [ 272 ]. The different combinations of JAK and STAT isoforms, along with the variety of receptors and ligands that can activate the signaling pathway make the cellular response to JAK/STAT signaling broad and, at the same time, an interesting target for drugs to block the proliferation of cancer cells [ 273 ]. The JAK/STAT signaling pathway is indeed involved in many cellular functions that are altered in cancer, such as cell differentiation, proliferation, stemness, regulation of apoptotic signaling, and modulation of the immune or inflammatory response [ 274 , 275 , 276 , 277 ]. In hepatocytes, JAK/STAT signaling can also modulate the metabolism by regulating gluconeogenesis [ 278 ]. In addition to the above-mentioned changes in growth-factor- and cytokine-mediated signaling, JAK/STAT signaling can be altered by activating mutations that can drive and/or maintain carcinogenesis [ 279 , 280 , 281 , 282 ]. A whole-genome analysis of primary HCC [ 283 ] revealed that 9.1% of patients carry activating mutations in JAK1, and a proteogenomic characterization of virus-associated liver cancers [ 64 ] showed that JAK2 is overexpressed in a subclass of HCC. Together with the Wnt pathway, JAK/STAT is the main oncogenic pathway in HCC [ 283 ]. JAK-specific inhibitors, such as tofacitinib [ 284 ], baricitinib [ 285 ], and upadacitinib [ 286 ], are currently approved for the treatment of rheumatoid arthritis and are effective in reducing cytokine-mediated inflammation [ 287 ]. Many JAK inhibitors are being tested in clinical trials for the treatment of cancer [ 288 ], mostly lymphoproliferative and myelodysplastic malignancies, and, to date, no clinical trial using JAK inhibitors has involved HCC patients [ 289 , 290 , 291 ]. There are some reports in the literature of the preclinical testing of JAK inhibitors on HCC cell lines or tumor-derived cells, generally showing a reduction in tumor cell proliferation and migration [ 292 , 293 , 294 , 295 , 296 ].

STAT3 is an emerging candidate for JAK/STAT-targeted therapy as its constitutive activation is associated with oncogenesis, metastasis, and drug resistance in various cancers, including HCC [ 297 , 298 ]. Nevertheless, there is no FDA- or EMA-approved drug that selectively targets STAT3. Some STAT3-specific inhibitors are currently being tested in clinical trials both as a single agent and in combination with other drugs. These include napabucasin [ 299 , 300 ], OPB-111077 [ 301 , 302 ], OPB-31121 [ 303 , 304 ], TT1-101 ( NCT03195699 ), and AZD9150 [ 305 , 306 ], which are also being tested in Phase I or II clinical trials in HCC. Preclinical studies have demonstrated the efficacy of STAT3 inhibitor molecules in improving radiosensitivity of HCC and in reducing proliferation and promoting apoptosis [ 307 ]. It is worth noting that STAT3 is one of the targets of sorafenib, a generic kinase inhibitor approved for the treatment of unresectable HCC, and that the inhibition of STAT3 is essential for the sensitization of HCC cells to an agonistic DR5 antibody (LBY135) and for TRAIL-induced apoptosis in TRAIL-resistant HCC cells [ 308 ].

Aberrant STAT3 activation in HCC is mainly mediated by interleukin-6 (IL-6) trans-signaling and is, therefore, commonly referred to as IL-6/STAT3 axis alteration [ 309 , 310 , 311 ]. In the TME of HCC, this pro-inflammatory interleukin is generally secreted by tumor-associated macrophages, as well as tumor cells [ 310 , 312 , 313 ]. IL-6 also favors fibroblasts to acquire a pro-tumoral phenotype (CAF, cancer associated fibroblasts) [ 314 ].

Moreover, several in vitro studies support that an elevated IL-6 level in the HCC TME promotes the development of resistance to sorafenib and anti-PD-L1 antibodies [ 315 , 316 , 317 ].

There are currently no IL-6 inhibitors in clinical trials for the treatment of HCC.

Clinically, several monoclonal antibodies have been shown to neutralize IL-6, such as siltuximab [ 318 ], sirukumab [ 319 ], and tocilizumab. The latter in particular has shown good results in the treatment of non-small-cell lung cancer [ 320 ], multiple myeloma [ 320 ], epithelial ovarian cancer [ 321 ], B-cell lymphoma [ 322 ], and renal cell carcinoma [ 323 ].

All in all, targeting the JAK/STAT metabolic pathway in HCC may be a useful therapeutic option, as it involves several oncogenic and progression-promoting mechanisms typical of HCC, such as chronic inflammation (Fibrosis is associated with oncogenesis and the development of HCC [ 324 , 325 ]), altered metabolism (STAT3 activation enhances the Warburg effect by promoting anaerobic glucose metabolism [ 326 ]), and angiogenesis [ 297 , 327 , 328 ].

3.6. PI3K/AKT/mTOR

The phosphatidylinositol-3 kinase (PI3K), protein kinase B (AKT), and mechanistic target of rapamycin (mTOR) are central control centers for many important cellular functions, such as proliferation, survival, migration, metabolism, and responses to stressors and drugs. Several upstream regulators and downstream effectors are involved in this complex signaling axis, each of which may play a role in carcinogenesis. PI3K belongs to a family of lipid kinases that are categorized into three groups based on their substrate specificity, structure, and mechanism (see [ 329 ] for a more detailed description of PI3K proteins). The activation of PI3K triggers the conversion from phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3), which serves as a secondary messenger to initiate the activation, by phosphorylation, of AKT mediated by PDK-1 or mTORC2. This process is highly tuned and can be antagonized by various phosphatases, including PTEN, a known tumor suppressor. Activated AKT phosphorylates and activates multiple downstream targets, including the RHEB protein, which is released and can activate mTOR. The activated mTOR protein can organize itself into two complexes: mTORC1 and mTORC2, the latter of which is exclusively dependent on PIP3 phosphorylation for its activation. PI3K-mediated mTORC2 activation can activate mTORC1 via AKT. A more detailed overview of PI3K/AKT/mTOR signaling can be found in [ 330 , 331 ].

Seventeen genes are involved in controlling the PI3A/AKT/mTOR signaling pathway: PIK3CA , PIK3R1 , PIK3R2 , PTEN , PDPK1 , AKT1 , AKT2 , FOXO1 , FOXO3 , MTOR , RICTOR , TSC1 , TSC2 , RHEB , AKT1S1 , RPTOR , and MLST8 . In cancer, PIK3CA is most frequently mutated, with mutations in AKT1, AKT2, and the proteins of the mTOR complex, except for RICTOR and mTOR, being relatively uncommon [ 332 ].

The PI3K/AKT/mTOR signaling pathway is altered in 51% of HCCs [ 333 ], with the most frequently mutated genes being PTEN (5%), PIK3CA (4%), MTOR (4%), and AKT2 (2%) [ 263 , 333 ]. According to Fujita et al. [ 64 ], SYK is selectively upregulated in the R1 proteomic class, RHEB is selectively upregulated in the R2 proteomic class, and AKT1 , LK1 , pS6K , and DUSP4 are selectively upregulated in the R3 proteomic class.

FDA-approved or investigational inhibitors of the PI3K/AKT/mTOR pathway are being tested for the treatment of HCC either in preclinical or clinical trials. Copanlisib, a PI3K inhibitor, is being tested in a clinical trial in combination with nivolumab ( NCT03735628 ) and has shown potent antiproliferative activity in an in vitro model in combination with sorafenib [ 334 ]. MK2206, an AKT inhibitor, is being tested in HCC patients who have not responded to prior therapy ( NCT01239355 ). Everolimus, an mTOR inhibitor, is used alone [ 335 ] or in combination with TACE ( NCT01239355 ) or sorafenib [ 336 ] in clinical trials in HCC patients. A dual mTORC1/mTORC2 inhibitor, CC-223, is being tested in HBV-positive HCC patients ( NCT03591965 ). Sapanisertib, an mTOR inhibitor, is being tested in advanced or metastatic HCC patients ( NCT02575339 ). A more detailed analysis of clinical trials targeting PI3K/AKT/mTOR in HCC can be found in [ 337 ].

To date, targeting PI3K/AKT/mTOR in HCC has yielded only partially positive results, mainly due to early onset drug resistance and cancer progression [ 337 ].

3.7. Wnt/β-Catenin

Wnt/β-catenin is a complex pathway that regulates several cellular functions. Canonical Wnt signaling is repressed in adult tissues by the intervention of several antagonists and inhibitors. Wnt1 and Wnt3a, ligands activating Wnt/β-catenin signaling, belong to a family of 19 proteins. Their activation requires lipid modification mediated by the porcupine O-acyltransferase (PORCN) protein. β-catenin, a structural protein in cell adhesion, is encoded by the CTNNB1 gene. In the absence of Wnt signaling, CTNNB1 is poorly expressed, and its translocation to the nucleus is impaired by a protein complex named the destruction complex, maintaining low β-catenin levels through proteasomal degradation.

Upon Wnt signaling activation, β-catenin becomes free from the scaffold protein AXIN and is released from the destruction complex. Cytosolic β-catenin can translocate to the nucleus and act as a scaffold for the formation of transcriptional factor complexes, activating the expression of downstream effectors of the Wnt/β-catenin signaling. A comprehensive description of the signaling pathway can be found in [ 338 ].

According to TCGA data, twenty-five genes are involved in Wnt signaling tumorigenesis and cancer progression. These include SFRP1, SFRP2, SFRP4, SFRP5, SOST, TCF7L1, TLE1, TLE2, TLE3, TLE4, WIF1, ZNRF3, CTNNB1, AMER1, APC, AXIN1, AXIN2, DKK1, DKK2, DKK3, DKK4, GSK3B, RNF43, TCF7, and TCF7L2 [ 263 ].

In hepatic cells, Wnt/β-catenin is activated under physiological conditions and is essential for hepatobiliary development and regeneration processes [ 339 ]. It is one of the most dysregulated pathways in HCC, with mutations detected in 62.5% of HCC samples [ 283 ]. The most frequent mutations in HCC involve CTNNB1 (15.9–30%), AXIN1 (4.5–8%), and APC (0.8–3%) [ 263 , 283 , 340 ]. DKK1 is considered as an early-stage HCC biomarker [ 341 , 342 ], and CTNNB1 is enriched in proteomic subclass 3 [ 64 ]. CTNNB1 mutations are significantly associated with telomerase reverse-transcriptase promoter (TERT) mutations [ 343 ]. The telomerase proteins are responsible for the maintenance of chromosomal and genomic integrity; correlation between CTNNB1 and TERT mutations in HCC may indicate a connection between CTNNB1 mutations and genomic instability [ 343 , 344 ].

Despite several Wnt/β-catenin inhibitors being selected and proven effective in blocking cancer proliferation in preclinical models, very few have reached the clinical trial stage, and none have gained FDA or EMA approval for cancer treatment [ 345 ]. Among the drugs tested in clinical trials, E7386, the first-in-class orally active β-catenin antagonist, is being tested in HCC in combination with lenvatinib ( NCT04008797 ) or pembrolizumab ( NCT05091346 ) [ 346 ]. CGX1321, a PORCN inhibitor, and DKN-01-mAb, a DKK1 inhibitor, are undergoing clinical trials in combination with other drugs in patients with advanced liver cancers ( NCT02675946 and NCT03645980 , respectively). OMP-54F28, an antagonist of the FZD8/Wnt complex, has been tested in Phase I clinical trials for the treatment of HCC ( NCT02069145 ).

A comprehensive review of preclinical studies targeting Wnt/β-catenin can be found in [ 341 , 342 ].

3.8. p53

The protein p53 is a transcription factor and regulates the expression of genes involved in the cell cycle’s arrest, apoptosis, and DNA repair [ 347 ]. In addition to its primary functions, p53 also plays an important role in other cellular and metabolic processes. A more detailed analysis of the functions of p53 can be found in [ 348 ]. Given its important role in vital cellular processes, the expression and function of p53 are highly regulated [ 349 , 350 ]. Under physiological and homeostatic conditions, the expression levels of p53 are very low, and its ability to translocate to the nucleus is regulated by various inhibitors. Among others, MDM2, an E3 ubiquitin ligase localized in the cell nucleus, plays a crucial role in maintaining low p53 levels [ 351 ].

The oncosuppressor gene TP53 is one of the most frequently mutated genes in cancer. In fact, somatic mutations in TP53 are found in about 34–50% of samples from cancer patients [ 263 , 352 ]. Mutations in TP53 are considered as driver mutations that lead to malignant transformation [ 353 ].

Although 70% of all TP53 alterations are missense mutations [ 354 ], alterations in the p53 signaling pathway may also depend on mutations in proteins involved in the negative feedback regulation of the p53 activity [ 355 ].

p53 is considered as a druggable target, and the main targeting strategies include the use of small molecules that induce the refolding of the mutant p53 and, thus, restore its pro-apoptotic activity; small-molecule inhibitors of MDM2–p53 interactions that block the aberrant degradation of p53 also in the presence of the wild-type p53 protein; and gene therapy aimed at reestablishing the normal levels and function of p53. A complete review of p53-targeting strategies can be found in [ 354 , 356 ].

In HCC, TP53 is mutated in 30.8–35.2% of patients [ 283 , 357 , 358 ], and TP53 mutations are significantly associated with reduced protein levels [ 64 ] and a poor prognosis [ 359 ]. To date, there are no specific clinical trials targeting p53 in HCC, but several molecules are being tested for the treatment of solid tumors: ASTX295 ( NCT03975387 ), HDM201 ( NCT04116541 ), idasanutlin MT ( NCT04589845 ), and milademetan MT (NCT0512397), which are small molecules that inhibit MDM2’s activity; PC14586 ( NCT04585750 ) and arsenic trioxide MT ( NCT04869475 ), two small molecules that target mutant p53; and Ad-p53, a p53-based gene therapy ( NCT03544723 ). Ad-p53, a recombinant human adenovirus p53, was approved by the China Food and Drug Administration (CFDA) in 2003 as the first gene therapy for the treatment of cancer [ 360 , 361 ]. A recent systematic review of 17 clinical trials in which Ad-p53 was used in combination with TACE for the treatment of HCC found that the addition of recombinant p53 resulted in improved overall survival and quality of life compared to standard monoagent TACE therapy [ 362 ]. Another study using Ad-p53 in combination with fractionated stereotactic radiotherapy showed improvement in the outcome of the combined therapy compared to fractionated stereotactic radiotherapy alone [ 363 ].

Given its prominent role in malignant transformation and cancer progression and its high mutation frequency in cancers [ 352 ], p53 is an attractive target in cancer treatment, as evidenced by the increasing number of studies on potential therapeutic approaches to restore the pro-apoptotic function of p53 [ 354 , 356 , 364 , 365 ]. Nevertheless, no p53-specific drug has yet received FDA or EMA approval for the treatment of cancer [ 354 , 365 ].

3.9. Cyclins and Cyclin-Dependent Kinases

The cell cycle’s progression is promoted, maintained, and regulated by the interplay of cyclins and specific cyclin-dependent kinases (CDKs), which, in turn, are controlled by a variety of extracellular and intracellular signaling [ 366 ]. CDKs are a family of 20 small proteins with serine–threonine kinase activity for which activation depends on their interaction with cyclins, a class of proteins for which the concentration varies greatly during each phase of the cell cycle [ 367 ]. CDK2, CDK4, and CDK6 are cell-cycle-related CDKs, while the others are involved in transcriptional regulation, the maintenance of genomic stability, and other biological processes [ 368 ]. The activation of the CDK–cyclin complex is tightly regulated and depends on the activity of specific phosphatases and CDK-activating kinases (CAKs) [ 366 ].

Given their role in controlling the cell cycle’s progression, the dysregulation of CDKs and cyclins is a hallmark of cancer and, therefore, of great interest as targets for cancer treatment [ 369 ]. In particular, CDK4 and CDK6, as well as cyclins D1 and E, are frequently altered in cancer [ 369 ].

According to whole-genome and exome sequencing data, CCND1 and CCNE1 , encoding cyclins D1 and E1, respectively, are amplified in 4.5% of HCC patients, while CDKN2A and CDKN2B , two negative regulators of CDKs, are deleted in 10.2% and 12.5% of patients, respectively [ 283 , 333 ]. Moreover, the overexpression of a set of cell cycle proteins comprising CDK1 and cyclin B1 was significantly associated with poor overall survival in HCC patients [ 64 ]. By proteomic profiling, WEE1, a negative regulator of the CDK1–cyclin B complex, was overexpressed in the R3 subclass comprising HCCs that were smaller in size and less invasive, but with poor immune infiltration [ 64 ].

CDKs are the primary target for cancer therapy against the cell cycle. The first molecules in this class were pan-CDK inhibitors (CDKi) [ 370 , 371 ], but their use was very limited and discontinued owing to their high toxicity [ 372 , 373 ]. Second-generation CDK inhibitors are much more selective for CDK4/6 and have fewer side effects [ 374 , 375 ]. Three CDKi molecules are approved by the EMA and FDA for the treatment of HR-positive, HER2-negative breast cancer: palbociclib [ 376 ], ribociclib [ 377 ], and abemaciclib [ 378 ]. In HCC, CDKi molecules have an antiproliferative activity when tested in preclinical models [ 379 , 380 , 381 , 382 , 383 ] and are being tested in clinical trials either alone or in combination with other therapeutics ( NCT01356628 , NCT02524119 , and NCT03781960 ), but the results are not yet available.

Targeting cell cycle regulators, such as CDKs, can be a valuable strategy to stop cancer cell proliferation and induce cell death, as proved by the improvement in the treatment of breast cancer using CDK4/6 inhibitors. A similar strategy can result in improved treatment of HCC subtypes in which cell cycle deregulation depends mostly on CDK/cyclin deregulation.

3.10. TGFβ Signaling

The TME is a complex environment that is grafted around the tumor, in which intricate interactions are established between cellular (e.g., tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs)) and noncellular (e.g., extracellular matrix (ECM) proteins, proteolytic enzymes, cytokines, and growth factors) elements, which cooperate to favor tumor growth and progression.

The need to identify therapeutic strategies that target the TME is becoming increasingly urgent given the fundamental role it plays in the development of drug resistance mechanisms and tumorigenesis. The TME of HCC is particularly hostile to immunotherapy, creating an immunosuppressive environment that easily undermines the efficacy of this type of therapeutic approach. Given the crucial role of TFGβ in the TME crosstalk, this section will focus on this signaling as a strong candidate target. A more detailed review analyzing other potential targets in the TME of HCC can be found in [ 206 ].

The TFGβ superfamily consists of 33 multifunctional cytokines, of which TGFβ1 represents the most abundant isoform. TFGβ signaling is critically involved in the regulation of multiple cellular processes controlling tissue homeostasis, including proliferation, differentiation, migration, and cell death. TFGβ signaling dysregulation is, therefore, detected in many diseases, including hepatocarcinoma [ 384 , 385 , 386 , 387 ].

TGFβ has two opposing roles in HCC development. In the early stages of the disease, it plays an inhibitory role in tumor growth by inducing apoptosis in cancer cells [ 388 , 389 , 390 ]. However, along the process, tumor cells become resistant to its inhibitory action, owing to the inactivation of the key components in the pathway or the hyperactivation of parallel pathways that counteract its inhibitory action. At this point, tumor cells begin to respond to its presence by inducing EMT, which increases their migratory capabilities and invasive potential [ 391 , 392 ]. In this process, the growth factors EGF and PDGF play an important role by activating an autocrine loop that increases the ability of the cells to overcome the pro-apoptotic effect of TFGβ [ 92 , 393 ]. Recent evidence has also been shown of a possible involvement of TFGβ in the metabolic reprogramming of tumor cells [ 394 ].

TFGβ plays an equally important role as a mediator among TME components throughout the cancer development process.

Among others, HSC-derived TGFβ is known to upregulate NNMT (N-methyltransferase) expression in HCC [ 395 ]. NNMT correlates with tumor stages and DFS in HCC, indicating its prognostic significance. Therefore, potential therapeutic strategies targeting NNMT in HCC may be worth exploring, including NNMT inhibitors and drug repurposing with statins, although further clinical studies are needed [ 396 , 397 ].

The idea for using TFGβ as a therapeutic target is becoming increasingly attractive. However, it is necessary to correctly identify patients where TFGβ is exerting a pro-tumoral action and who could, therefore, benefit from such a therapeutic approach. Several studies conducted in vitro, in vivo, and in HCC-patient-derived material allowed the identification of the so-called “late TFGβ signature”, which is the selective overexpressions of CXCR4, CD44, SMAD7, or CTLC genes in concurrence with the TFGβ one. This could be of great help in the identification of patients who could benefit from an anti-TFGβ treatment [ 243 , 392 , 398 , 399 , 400 , 401 ].

Several TFG-β inhibitors are available and have different mechanisms of action. Some suppress the production of TFGβ itself, others inhibit its activity, and others block either its interaction with the receptor or the kinase activity of the receptor itself. These inhibitors have shown promising anti-tumor activity in several in vivo studies, and some are also being tested in clinical trials in patients with advanced HCC ( NCT01246986 , NCT02906397 , NCT02423343 , and NCT02699515 ) [ 387 , 402 , 403 ].

Recently, a CAR-T called PSMA–TGFβRDN has also been developed to neutralize TGFβ’s pro-tumoral activity. T-cells engineered with this CAR have shown increased proliferative capacity and persistence in vivo, as well as increased cytokine release and reduced exhaustion. CAR–PSMA–TGFβRDN is being tested in Phase I clinical trials in patients with advanced or relapsed prostate cancer, though no clinical trial has been planned yet in patients with HCC ( NCT03089203 and NCT04227275 ) [ 404 ].

4. Conclusions

The identification of effective therapeutic targets in HCC remains an open challenge in cancer research. The complexity of the tumor ecosystem, along with its distinctive immunosuppressive microenvironment, has made the development of effective targeting strategies difficult to achieve. Although data collection on the mRNA expression levels from tumor samples remains a powerful tool, it is not exhaustive when searching for new potential targets. In fact, during the writing of this review, it became increasingly clear that in the search for new targets, there is a need for an in-depth analysis at the level of protein expression as well as of the activation status of the proteins involved in the major signaling pathways described above.

The roles of most of them and their potential as targets for new therapeutic options for HCC have been examined in this review. However, there are many other valid candidates that need to be thoroughly examined for their roles in HCC tumorigenesis, cancer progression, and prognosis.

In conclusion, in this review, we have discussed the currently available approaches to target this difficult-to-treat cancer and summarized potential emerging protein targets, summarized in Table 2 and Table 3 , with the understanding that much work remains to be done to gain a clearer view of the global situation to establish more effective targeting strategies.

Acknowledgments

We thank the Immuno-HUB members for the interesting scientific discussion.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers16050901/s1 , File S1: ImmunoHUB Author List.

Author Contributions

G.P. conceptualized the study, wrote the manuscript, and collected data for clinical trials. C.S. conceptualized the study, wrote the manuscript, provided financial support, and edited all the figures. The Immuno-HUB consortium took care of project Administration and Funding Acquisition. M.M. wrote the manuscript, collected data for clinical trials, and created all the original figures. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Llovet J.M. Zucman-Rossi J. Pikarsky E. Sangro B. Schwartz M. Sherman M. Gores G. Hepatocellular Carcinoma Nat. Rev. Dis. Prim. 2016 2 16018 10.1038/nrdp.2016.18 27158749

2. Russo F.P. Zanetto A. Pinto E. Battistella S. Penzo B. Burra P. Farinati F. Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand? Int. J. Mol. Sci. 2022 23 500 10.3390/ijms23010500 35008926 PMC8745141

3. Janevska D. Chaloska-Ivanova V. Janevski V. Hepatocellular Carcinoma: Risk Factors, Diagnosis and Treatment Open Access Maced. J. Med. Sci. 2015 3 732 736 10.3889/oamjms.2015.111 27275318 PMC4877918

4. Bogentoft C. Ericsson O. Kvist M. Danielsson B. Studies on the Medicinal Chemistry of Oxoquinazolines. XI. Synthesis of 1-Methyl-3-Substituted 1,2,3,4-Tetrahydro-4-Oxoquinazolines Acta Pharm. Suec. 1971 8 667 670 5139741

5. Gosalia A.J. Martin P. Jones P.D. Advances and Future Directions in the Treatment of Hepatocellular Carcinoma Gastroenterol. Hepatol. 2017 13 398 410 PMC5572970 28867968

6. Ju M.R. Yopp A.C. Evolving Thresholds for Liver Transplantation in Hepatocellular Carcinoma: A Western Experience Ann. Gastroenterol. Surg. 2020 4 208 215 10.1002/ags3.12316 32490334 PMC7240148

7. Ikeda M. Morizane C. Ueno M. Okusaka T. Ishii H. Furuse J. Chemotherapy for Hepatocellular Carcinoma: Current Status and Future Perspectives Jpn. J. Clin. Oncol. 2018 48 103 114 10.1093/jjco/hyx180 29253194

8. Chen C. Wang Z. Ding Y. Qin Y. Tumor Microenvironment-Mediated Immune Evasion in Hepatocellular Carcinoma Front. Immunol. 2023 14 1133308 10.3389/fimmu.2023.1133308 36845131 PMC9950271

9. Wang Z. Wang Y. Gao P. Ding J. Immune Checkpoint Inhibitor Resistance in Hepatocellular Carcinoma Cancer Lett. 2023 555 216038 10.1016/j.canlet.2022.216038 36529238

10. Makary M.S. Khandpur U. Cloyd J.M. Mumtaz K. Dowell J.D. Locoregional Therapy Approaches for Hepatocellular Carcinoma: Recent Advances and Management Strategies Cancers 2020 12 1914 10.3390/cancers12071914 32679897 PMC7409274

11. Iyer R. Fetterly G. Lugade A. Thanavala Y. Sorafenib: A Clinical and Pharmacologic Review Expert Opin. Pharmacother. 2010 11 1943 1955 10.1517/14656566.2010.496453 20586710

12. Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.-F. de Oliveira A.C. Santoro A. Raoul J.-L. Forner A. Sorafenib in Advanced Hepatocellular Carcinoma N. Engl. J. Med. 2008 359 378 390 10.1056/NEJMoa0708857 18650514

13. Parikh N.D. Marshall V.D. Singal A.G. Nathan H. Lok A.S. Balkrishnan R. Shahinian V. Survival and Cost-Effectiveness of Sorafenib Therapy in Advanced Hepatocellular Carcinoma: An Analysis of the SEER-Medicare Database Hepatology 2017 65 122 133 10.1002/hep.28881 27770556

14. Zhang X. Cai L. Fang J. Chen F. Pan F. Zhang K. Huang Q. Huang Y. Li D. Lv L. Efficacy and Safety of Transarterial Chemoembolization plus Sorafenib in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation Front. Oncol. 2022 12 1101351 10.3389/fonc.2022.1101351 36713526 PMC9880524

15. Zhang L. Hu P. Chen X. Bie P. Transarterial Chemoembolization (TACE) plus Sorafenib versus TACE for Intermediate or Advanced Stage Hepatocellular Carcinoma: A Meta-Analysis PLoS ONE 2014 9 e100305 10.1371/journal.pone.0100305 24945380 PMC4063775

16. Lencioni R. Llovet J.M. Han G. Tak W.Y. Yang J. Guglielmi A. Paik S.W. Reig M. Kim D.Y. Chau G.Y. Sorafenib or Placebo plus TACE with Doxorubicin-Eluting Beads for Intermediate Stage HCC: The SPACE Trial J. Hepatol. 2016 64 1090 1098 10.1016/j.jhep.2016.01.012 26809111

17. Alturki N.A. Review of the Immune Checkpoint Inhibitors in the Context of Cancer Treatment J. Clin. Med. 2023 12 4301 10.3390/jcm12134301 37445336 PMC10342855

18. Herbst R.S. Soria J.C. Kowanetz M. Fine G.D. Hamid O. Gordon M.S. Sosman J.A. McDermott D.F. Powderly J.D. Gettinger S.N. Predictive Correlates of Response to the Anti-PD-L1 Antibody MPDL3280A in Cancer Patients Nature 2014 515 563 567 10.1038/nature14011 25428504 PMC4836193

19. Kudo M. Durvalumab plus Tremelimumab in Unresectable Hepatocellular Carcinoma Hepatobiliary Surg. Nutr. 2022 11 592 596 10.21037/hbsn-22-143 36016731 PMC9396100

20. Finn R.S. Ryoo B.Y. Merle P. Kudo M. Bouattour M. Lim H.Y. Breder V. Edeline J. Chao Y. Ogasawara S. Pembrolizumab as Second-Line Therapy in Patients with Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial J. Clin. Oncol. 2020 38 193 202 10.1200/JCO.19.01307 31790344

21. Yau T. Park J.W. Finn R.S. Cheng A.L. Mathurin P. Edeline J. Kudo M. Harding J.J. Merle P. Rosmorduc O. Nivolumab versus Sorafenib in Advanced Hepatocellular Carcinoma (CheckMate 459): A Randomised, Multicentre, Open-Label, Phase 3 Trial Lancet Oncol. 2022 23 77 90 10.1016/S1470-2045(21)00604-5 34914889

22. Sun H. Song X. Li C. Li Q. Liu S. Deng N. Humanized Disulfide-Stabilized Diabody against Fibroblast Growth Factor-2 Inhibits PD-L1 Expression and Epithelial-Mesenchymal Transition in Hepatoma Cells through STAT3 IUBMB Life 2023 75 957 968 10.1002/iub.2766 37489553

23. Yuan Q. Liang Q. Sun Z. Yuan X. Hou W. Wang Y. Wang H. Yu M. Development of Bispecific Anti-c-Met/PD-1 Diabodies for the Treatment of Solid Tumors and the Effect of c-Met Binding Affinity on Efficacy Oncoimmunology 2021 10 1914954 10.1080/2162402X.2021.1914954 34350059 PMC8296967

24. Jiang W. Li T. Guo J. Wang J. Jia L. Shi X. Yang T. Jiao R. Wei X. Feng Z. Bispecific C-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma Front. Oncol. 2021 11 546586 10.3389/fonc.2021.546586 33777728 PMC7987916

25. Dahlgren D. Lennernäs H. Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective Molecules 2020 25 2861 10.3390/molecules25122861 32575828 PMC7356544

26. Huang L.R. Hsu H.C. Cloning and Expression of CD24 Gene in Human Hepatocellular Carcinoma: A Potential Early Tumor Marker Gene Correlates with P53 Mutation and Tumor Differentiation Cancer Res. 1995 55 4717 4721 7553654

27. Zhang Y.-F. Ho M. Humanization of High-Affinity Antibodies Targeting Glypican-3 in Hepatocellular Carcinoma Sci. Rep. 2016 6 33878 10.1038/srep33878 27667400 PMC5036187

28. Fu Y. Urban D.J. Nani R.R. Zhang Y.F. Li N. Fu H. Shah H. Gorka A.P. Guha R. Chen L. Glypican-3-Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma Hepatology 2019 70 563 576 10.1002/hep.30326 30353932 PMC6482108

29. Ma Z. He H. Sun F. Xu Y. Huang X. Ma Y. Zhao H. Wang Y. Wang M. Zhang J. Selective Targeted Delivery of Doxorubicin via Conjugating to Anti-CD24 Antibody Results in Enhanced Antitumor Potency for Hepatocellular Carcinoma Both in Vitro and in Vivo J. Cancer Res. Clin. Oncol. 2017 143 1929 1940 10.1007/s00432-017-2436-0 28536738 PMC11819455

30. Sun F. Wang T. Jiang J. Wang Y. Ma Z. Li Z. Han Y. Pan M. Cai J. Wang M. Engineering a High-Affinity Humanized Anti-CD24 Antibody to Target Hepatocellular Carcinoma by a Novel CDR Grafting Design Oncotarget 2017 8 51238 51252 10.18632/oncotarget.17228 28881644 PMC5584245

31. Mullard A. FDA Approves First CAR T Therapy Nat. Rev. Drug Discov. 2017 16 669 10.1038/nrd.2017.196 28959944

32. Ozer M. Goksu S.Y. Akagunduz B. George A. Sahin I. Adoptive Cell Therapy in Hepatocellular Carcinoma: A Review of Clinical Trials Cancers 2023 15 1808 10.3390/cancers15061808 36980692 PMC10046758

33. Tseng H.-C. Xiong W. Badeti S. Yang Y. Ma M. Liu T. Ramos C.A. Dotti G. Fritzky L. Jiang J.-G. Efficacy of Anti-CD147 Chimeric Antigen Receptors Targeting Hepatocellular Carcinoma Nat. Commun. 2020 11 4810 10.1038/s41467-020-18444-2 32968061 PMC7511348

34. Lian C. Guo Y. Zhang J. Chen X. Peng C. Targeting CD147 Is a Novel Strategy for Antitumor Therapy Curr. Pharm. Des. 2017 23 4410 4421 10.2174/1381612823666170710144759 28699528

35. Landras A. de Moura C.R. Jouenne F. Lebbe C. Menashi S. Mourah S. CD147 Is a Promising Target of Tumor Progression and a Prognostic Biomarker Cancers 2019 11 1803 10.3390/cancers11111803 31744072 PMC6896083

36. Zhou R. Yazdanifar M. Das Roy L. Whilding L.M. Gavrill A. Maher J. Mukherjee P. CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth Front. Immunol. 2019 10 1149 10.3389/fimmu.2019.01149 31178870 PMC6543840

37. Dai H. Tong C. Shi D. Chen M. Guo Y. Chen D. Han X. Wang H. Wang Y. Shen P. Efficacy and Biomarker Analysis of CD133-Directed CAR T Cells in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Trial Oncoimmunology 2020 9 1846926 10.1080/2162402X.2020.1846926 33312759 PMC7714531

38. Jiang Z. Jiang X. Chen S. Lai Y. Wei X. Li B. Lin S. Wang S. Wu Q. Liang Q. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma Front. Immunol. 2016 7 690 10.3389/fimmu.2016.00690 28123387 PMC5225101

39. Liu H. Yang C. Lu W. Zeng Y. Prognostic Significance of Glypican-3 Expression in Hepatocellular Carcinoma: A Meta-Analysis Medicine 2018 97 e9702 10.1097/MD.0000000000009702 29369198 PMC5794382

40. Hu P. Ke C. Guo X. Ren P. Tong Y. Luo S. He Y. Wei Z. Cheng B. Li R. Both Glypican-3/Wnt/β-Catenin Signaling Pathway and Autophagy Contributed to the Inhibitory Effect of Curcumin on Hepatocellular Carcinoma Dig. Liver Dis. 2019 51 120 126 10.1016/j.dld.2018.06.012 30001951

41. Shi D. Shi Y. Kaseb A.O. Qi X. Zhang Y. Chi J. Lu Q. Gao H. Jiang H. Wang H. Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials Clin. Cancer Res. 2020 26 3979 3989 10.1158/1078-0432.CCR-19-3259 32371538

42. Li W. Guo L. Rathi P. Marinova E. Gao X. Wu M.F. Liu H. Dotti G. Gottschalk S. Metelitsa L.S. Redirecting T Cells to Glypican-3 with 4-1BB Zeta Chimeric Antigen Receptors Results in Th1 Polarization and Potent Antitumor Activity Hum. Gene Ther. 2017 28 437 448 10.1089/hum.2016.025 27530312 PMC5444493

43. Pang N. Shi J. Qin L. Chen A. Tang Y. Yang H. Huang Y. Wu Q. Li X. He B. IL-7 and CCL19-Secreting CAR-T Cell Therapy for Tumors with Positive Glypican-3 or Mesothelin J. Hematol. Oncol. 2021 14 118 10.1186/s13045-021-01128-9 34325726 PMC8323212

44. Liu H. Xu Y. Xiang J. Long L. Green S. Yang Z. Zimdahl B. Lu J. Cheng N. Horan L.H. Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer Clin. Cancer Res. 2017 23 478 488 10.1158/1078-0432.CCR-16-1203 27535982

45. Xue J. Cao Z. Cheng Y. Wang J. Liu Y. Yang R. Li H. Jiang W. Li G. Zhao W. Acetylation of Alpha-Fetoprotein Promotes Hepatocellular Carcinoma Progression Cancer Lett. 2020 471 12 26 10.1016/j.canlet.2019.11.043 31811908

46. Li W. Liu K. Chen Y. Zhu M. Li M. Role of Alpha-Fetoprotein in Hepatocellular Carcinoma Drug Resistance Curr. Med. Chem. 2021 28 1126 1142 10.2174/0929867327999200729151247 32729413

47. Meng F. Zhao J. Tan A.T. Hu W. Wang S.Y. Jin J. Wu J. Li Y. Shi L. Fu J.L. Immunotherapy of HBV-Related Advanced Hepatocellular Carcinoma with Short-Term HBV-Specific TCR Expressed T Cells: Results of Dose Escalation, Phase I Trial Hepatol. Int. 2021 15 1402 1412 10.1007/s12072-021-10250-2 34850325 PMC8651587

48. Tan A.T. Yang N. Lee Krishnamoorthy T. Oei V. Chua A. Zhao X. Tan H.S. Chia A. Le Bert N. Low D. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy Gastroenterology 2019 156 1862 1876.e9 10.1053/j.gastro.2019.01.251 30711630

49. Sun B. Yang D. Dai H. Liu X. Jia R. Cui X. Li W. Cai C. Xu J. Zhao X. Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells Cancer Immunol. Res. 2019 7 1813 1823 10.1158/2326-6066.CIR-19-0026 31484657

50. Zhang J. Basher F. Wu J.D. NKG2D Ligands in Tumor Immunity: Two Sides of a Coin Front. Immunol. 2015 6 97 10.3389/fimmu.2015.00097 25788898 PMC4349182

51. Oliviero B. Varchetta S. Mele D. Pessino G. Maiello R. Falleni M. Tosi D. Donadon M. Soldani C. Franceschini B. MICA/B-Targeted Antibody Promotes NK Cell-Driven Tumor Immunity in Patients with Intrahepatic Cholangiocarcinoma Oncoimmunology 2022 11 2035919 10.1080/2162402X.2022.2035919 35223192 PMC8865231

52. Mendelsohn C.L. Wimmer E. Racaniello V.R. Cellular Receptor for Poliovirus: Molecular Cloning, Nucleotide Sequence, and Expression of a New Member of the Immunoglobulin Superfamily Cell 1989 56 855 865 10.1016/0092-8674(89)90690-9 2538245

53. Molfetta R. Zitti B. Lecce M. Milito N.D. Stabile H. Fionda C. Cippitelli M. Gismondi A. Santoni A. Paolini R. CD155: A Multi-Functional Molecule in Tumor Progression Int. J. Mol. Sci. 2020 21 922 10.3390/ijms21030922 32019260 PMC7037299

54. Mantovani S. Varchetta S. Mele D. Maiello R. Donadon M. Soldani C. Franceschini B. Torzilli G. Tartaglia G. Maestri M. Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells Cancers 2022 14 4060 10.3390/cancers14164060 36011052 PMC9406989

55. Freed-Pastor W.A. Lambert L.J. Ely Z.A. Pattada N.B. Bhutkar A. Eng G. Mercer K.L. Garcia A.P. Lin L. Rideout W.M. The CD155/TIGIT Axis Promotes and Maintains Immune Evasion in Neoantigen-Expressing Pancreatic Cancer Cancer Cell 2021 39 1342 1360.e14 10.1016/j.ccell.2021.07.007 34358448 PMC8511341

56. Yang F. Zhang F. Ji F. Chen J. Li J. Chen Z. Hu Z. Guo Z. Self-Delivery of TIGIT-Blocking ScFv Enhances CAR-T Immunotherapy in Solid Tumors Front. Immunol. 2023 14 1175920 10.3389/fimmu.2023.1175920 37359558 PMC10287952

57. Liu M. Jiang L. Guan X.Y. The Genetic and Epigenetic Alterations in Human Hepatocellular Carcinoma: A Recent Update Protein Cell 2014 5 673 691 10.1007/s13238-014-0065-9 24916440 PMC4145080

58. Dimri M. Satyanarayana A. Molecular Signaling Pathways and Therapeutic Targets in Hepatocellular Carcinoma Cancers 2020 12 491 10.3390/cancers12020491 32093152 PMC7072513

59. Takahashi Y. Nishioka K. Therapeutic Approaches Targeting Tumor Vasculature in Gastrointestinal Cancers Front. Biosci. 2011 3 541 548 10.2741/e268 21196333

60. Chuma M. Terashita K. Sakamoto N. New Molecularly Targeted Therapies against Advanced Hepatocellular Carcinoma: From Molecular Pathogenesis to Clinical Trials and Future Directions Hepatol. Res. 2015 45 E1 E11 10.1111/hepr.12459 25472913

61. Lee Y.H. Seo D. Choi K.J. Andersen J.B. Won M.A. Kitade M. Gómez-Quiroz L.E. Judge A.D. Marquardt J.U. Raggi C. Antitumor Effects in Hepatocarcinoma of Isoform-Selective Inhibition of HDAC2 Cancer Res. 2014 74 4752 4761 10.1158/0008-5472.CAN-13-3531 24958469 PMC4155016

62. Dimri M. Bilogan C. Pierce L.X. Naegele G. Vasanji A. Gibson I. McClendon A. Tae K. Sakaguchi T.F. Three-Dimensional Structural Analysis Reveals a Cdk5-Mediated Kinase Cascade Regulating Hepatic Biliary Network Branching in Zebrafish Development 2017 144 2595 2605 10.1242/dev.147397 28720653 PMC5536925

63. Elattar S. Dimri M. Satyanarayana A. The Tumor Secretory Factor ZAG Promotes White Adipose Tissue Browning and Energy Wasting FASEB J. 2018 32 4727 4743 10.1096/fj.201701465RR 29570397 PMC6266632

64. Fujita M. Chen M.J.M. Siwak D.R. Sasagawa S. Oosawa-Tatsuguchi A. Arihiro K. Ono A. Miura R. Maejima K. Aikata H. Proteo-Genomic Characterization of Virus-Associated Liver Cancers Reveals Potential Subtypes and Therapeutic Targets Nat. Commun. 2022 13 6481 10.1038/s41467-022-34249-x 36309506 PMC9617926

65. Blume-Jensen P. Hunter T. Oncogenic Kinase Signalling Nature 2001 411 355 365 10.1038/35077225 11357143

66. Ito Y. Takeda T. Sakon M. Tsujimoto M. Higashiyama S. Noda K. Miyoshi E. Monden M. Matsuura N. Expression and Clinical Significance of Erb-B Receptor Family in Hepatocellular Carcinoma Br. J. Cancer 2001 84 1377 1383 10.1054/bjoc.2000.1580 11355950 PMC2363640

67. Jorissen R.N. Walker F. Pouliot N. Garrett T.P.J. Ward C.W. Burgess A.W. Epidermal Growth Factor Receptor: Mechanisms of Activation and Signalling Exp. Cell Res. 2003 284 31 53 10.1016/S0014-4827(02)00098-8 12648464

68. Citri A. Yarden Y. EGF-ERBB Signalling: Towards the Systems Level Nat. Rev. Mol. Cell Biol. 2006 7 505 516 10.1038/nrm1962 16829981

69. Schneider M.R. Wolf E. The Epidermal Growth Factor Receptor Ligands at a Glance J. Cell. Physiol. 2009 218 460 466 10.1002/jcp.21635 19006176

70. Komposch K. Sibilia M. EGFR Signaling in Liver Diseases Int. J. Mol. Sci. 2015 17 30 10.3390/ijms17010030 26729094 PMC4730276

71. Yarden Y. Shilo B.-Z. SnapShot: EGFR Signaling Pathway Cell 2007 131 1018 10.1016/j.cell.2007.11.013 18045542

72. Buckley A.F. Burgart L.J. Sahai V. Kakar S. Epidermal Growth Factor Receptor Expression and Gene Copy Number in Conventional Hepatocellular Carcinoma Am. J. Clin. Pathol. 2008 129 245 251 10.1309/WF10QAAED3PP93BH 18208805

73. Moon W.S. Park H.S. Yu K.H. Park M.Y. Kim K.R. Jang K.Y. Kim J.S. Cho B.H. Expression of Betacellulin and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma: Implications for Angiogenesis Hum. Pathol. 2006 37 1324 1332 10.1016/j.humpath.2006.04.022 16949929

74. Lanaya H. Natarajan A. Komposch K. Li L. Amberg N. Chen L. Wculek S.K. Hammer M. Zenz R. Peck-Radosavljevic M. EGFR Has a Tumour-Promoting Role in Liver Macrophages during Hepatocellular Carcinoma Formation Nat. Cell Biol. 2014 16 972 981 10.1038/ncb3031 25173978 PMC4183558

75. Gao J. Huo Z. Song X. Shao Q. Ren W. Huang X. Zhou S. Tang X. EGFR Mediates Epithelial-mesenchymal Transition through the Akt/GSK-3β/Snail Signaling Pathway to Promote Liver Cancer Proliferation and Migration Oncol. Lett. 2024 27 59 10.3892/ol.2023.14192 38192662 PMC10773224

76. Schiffer E. Housset C. Cacheux W. Wendum D. Desbois-Mouthon C. Rey C. Clergue F. Poupon R. Barbu V. Rosmorduc O. Gefitinib, an EGFR Inhibitor, Prevents Hepatocellular Carcinoma Development in the Rat Liver with Cirrhosis Hepatology 2005 41 307 314 10.1002/hep.20538 15660382

77. Fuchs B.C. Hoshida Y. Fujii T. Wei L. Yamada S. Lauwers G.Y. Mcginn C.M. Deperalta D.K. Chen X. Kuroda T. Epidermal Growth Factor Receptor Inhibition Attenuates Liver Fibrosis and Development of Hepatocellular Carcinoma Hepatology 2014 59 1577 1590 10.1002/hep.26898 24677197 PMC4086837

78. López-Luque J. Caballero-Díaz D. Martinez-Palacián A. Roncero C. Moreno-Càceres J. García-Bravo M. Grueso E. Fernández A. Crosas-Molist E. García-Álvaro M. Dissecting the Role of Epidermal Growth Factor Receptor Catalytic Activity during Liver Regeneration and Hepatocarcinogenesis Hepatology 2016 63 604 619 10.1002/hep.28134 26313466

79. Sanoff H.K. Bernard S. Goldberg R.M. Morse M.A. Garcia R. Woods L. Moore D.T. O’Neil B.H. Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab for Advanced Hepatocellular Carcinoma Gastrointest. Cancer Res. 2011 4 78 83 22043322 PMC3201640

80. Zhu A.X. Stuart K. Blaszkowsky L.S. Muzikansky A. Reitberg D.P. Clark J.W. Enzinger P.C. Bhargava P. Meyerhardt J.A. Horgan K. Phase 2 Study of Cetuximab in Patients with Advanced Hepatocellular Carcinoma Cancer 2007 110 581 589 10.1002/cncr.22829 17583545

81. Berasain C. Ujue Latasa M. Urtasun R. Goñi S. Elizalde M. Garcia-Irigoyen O. Azcona M. Prieto J. Avila M.A. Epidermal Growth Factor Receptor (EGFR) Crosstalks in Liver Cancer Cancers 2011 3 2444 2461 10.3390/cancers3022444 24212818 PMC3757426

82. Chen L. Hodges R.R. Funaki C. Zoukhri D. Gaivin R.J. Perez D.M. Dartt D.A. Effects of Alpha1D-Adrenergic Receptors on Shedding of Biologically Active EGF in Freshly Isolated Lacrimal Gland Epithelial Cells Am. J. Physiol. Cell Physiol. 2006 291 C946 C956 10.1152/ajpcell.00014.2006 16760267 PMC2151204

83. Ally A. Balasundaram M. Carlsen R. Chuah E. Clarke A. Dhalla N. Holt R.A. Jones S.J.M. Lee D. Ma Y. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma Cell 2017 169 1327 1341.e23 10.1016/j.cell.2017.05.046 28622513 PMC5680778

84. Dubuisson L. Monvoisin A. Nielsen B.S. Le Bail B. Bioulac-Sage P. Rosenbaum J. Expression and Cellular Localization of the Urokinase-Type Plasminogen Activator and Its Receptor in Human Hepatocellular Carcinoma J. Pathol. 2000 190 190 195 10.1002/(SICI)1096-9896(200002)190:2<190::AID-PATH511>3.0.CO;2-H 10657018

85. Zheng Q. Tang Z. Wu Z. Shi D. Song H. Inhibitor of Plasminogen Activator 1 (PAI-1) in Hepatocellular Carcinoma Zhonghua Wai Ke Za Zhi 1998 36 474 476 11825444

86. Zheng Q. Tang Z. Wu Z. Urokinase-Type Plasminogen Activator (UPA), UPA Receptor (UPA-R) and Inhibitors (PA I -1) Expression in Hepatocellular Carcinoma in Relation to Cancer Invasion/Metastasis and Prognosis Zhonghua Zhong Liu Za Zhi 1998 20 57 59 10921061

87. Zhai B.T. Tian H. Sun J. Zou J.B. Zhang X.F. Cheng J.X. Shi Y.J. Fan Y. Guo D.Y. Urokinase-Type Plasminogen Activator Receptor (UPAR) as a Therapeutic Target in Cancer J. Transl. Med. 2022 20 135 10.1186/s12967-022-03329-3 35303878 PMC8932206

88. Baart V.M. van der Horst G. Deken M.M. Bhairosingh S.S. Schomann T. Sier V.Q. van der Mark M.H. Iamele L. de Jonge H. Resnati M. A Multimodal Molecular Imaging Approach Targeting Urokinase Plasminogen Activator Receptor for the Diagnosis, Resection and Surveillance of Urothelial Cell Carcinoma Eur. J. Cancer 2021 146 11 20 10.1016/j.ejca.2021.01.001 33561783

89. Cuesta Á.M. Palao N. Bragado P. Gutierrez-Uzquiza A. Herrera B. Sánchez A. Porras A. New and Old Key Players in Liver Cancer Int. J. Mol. Sci. 2023 24 17152 10.3390/ijms242417152 38138981 PMC10742790

90. Lee G.H. Fausto N. Development of Liver Tumors in Transforming Growth Factor a Transgenic Mice Cancer Res. 1992 52 5162 5170 1327502

91. Zambreg I. Assouline B. Housset C. Schiffer E. Overexpression of TGF-α and EGFR, a Key Event in Liver Carcinogenesis, Is Induced by Hypoxia Specifically in Hepatocytes Gastroenterol. Hepatol. Endosc. 2019 4 1 4 10.15761/GHE.1000183

92. Caja L. Sancho P. Bertran E. Fabregat I. Dissecting the Effect of Targeting the Epidermal Growth Factor Receptor on TGF-β-Induced-Apoptosis in Human Hepatocellular Carcinoma Cells J. Hepatol. 2011 55 351 358 10.1016/j.jhep.2010.10.041 21147185

93. Elmas A. Lujambio A. Huang K.-L. Proteomic Analyses Identify Therapeutic Targets in Hepatocellular Carcinoma Front. Oncol. 2022 12 814120 10.3389/fonc.2022.814120 35433463 PMC9006883

94. Chen J.Y. Chen Y.J. Yen C.J. Chen W.S. Huang W.C. HBx Sensitizes Hepatocellular Carcinoma Cells to Lapatinib by Up-Regulating ErbB3 Oncotarget 2016 7 473 489 10.18632/oncotarget.6337 26595522 PMC4808012

95. Shi D.M. Li L.X. Bian X.Y. Shi X.J. Lu L.L. Zhou H.X. Pan T.J. Zhou J. Fan J. Wu W.Z. MiR-296-5p Suppresses EMT of Hepatocellular Carcinoma via Attenuating NRG1/ERBB2/ERBB3 Signaling J. Exp. Clin. Cancer Res. 2018 37 294 10.1186/s13046-018-0957-2 30486894 PMC6264612

96. Andrae J. Gallini R. Betsholtz C. Role of Platelet-Derived Growth Factors in Physiology and Medicine Genes Dev. 2008 22 1276 1312 10.1101/gad.1653708 18483217 PMC2732412

97. Heldin C.H. Östman A. Rönnstrand L. Signal Transduction via Platelet-Derived Growth Factor Receptors Biochim. Biophys. Acta 1998 1378 F79 F113 10.1016/S0304-419X(98)00015-8 9739761

98. Birge R.B. Kalodimos C. Inagaki F. Tanaka S. Crk and CrkL Adaptor Proteins: Networks for Physiological and Pathological Signaling Cell Commun. Signal. 2009 7 13 10.1186/1478-811X-7-13 19426560 PMC2689226

99. Eriksson A. Nånberg E. Rönnstrand L. Engström U. Hellman U. Rupp E. Carpenter G. Heldin C.H. Claesson-Welsh L. Demonstration of Functionally Different Interactions between Phospholipase C-Gamma and the Two Types of Platelet-Derived Growth Factor Receptors J. Biol. Chem. 1995 270 7773 7781 10.1074/JBC.270.13.7773 7535778

100. Lin Y. Lin G. Fang W. Zhu H. Chu K. Increased Expression of Annexin A1 Predicts Poor Prognosis in Human Hepatocellular Carcinoma and Enhances Cell Malignant Phenotype Med. Oncol. 2014 31 327 10.1007/s12032-014-0327-7 25412936

101. Bishayee S. Ross A.H. Womer R. Scher C.D. Purified Human Platelet-Derived Growth Factor Receptor Has Ligand-Stimulated Tyrosine Kinase Activity Proc. Natl. Acad. Sci. USA 1986 83 6756 6760 10.1073/pnas.83.18.6756 3018745 PMC386588

102. Tallquist M. Kazlauskas A. PDGF Signaling in Cells and Mice Cytokine Growth Factor Rev. 2004 15 205 213 10.1016/j.cytogfr.2004.03.003 15207812

103. Ekman S. Thuresson E.R. Heldin C.H. Rönnstrand L. Increased Mitogenicity of an Alphabeta Heterodimeric PDGF Receptor Complex Correlates with Lack of RasGAP Binding Oncogene 1999 18 2481 2488 10.1038/sj.onc.1202606 10229199

104. Papadopoulos N. Lennartsson J. The PDGF/PDGFR Pathway as a Drug Target Mol. Asp. Med. 2018 62 75 88 10.1016/j.mam.2017.11.007 29137923

105. Ng F. Boucher S. Koh S. Sastry K.S.R. Chase L. Lakshmipathy U. Choong C. Yang Z. Vemuri M.C. Rao M.S. PDGF, TGF-Beta, and FGF Signaling Is Important for Differentiation and Growth of Mesenchymal Stem Cells (MSCs): Transcriptional Profiling Can Identify Markers and Signaling Pathways Important in Differentiation of MSCs into Adipogenic, Chondrogenic, and Osteogenic Lineages Blood 2008 112 295 307 10.1182/BLOOD-2007-07-103697 18332228

106. Heldin C.H. Lennartsson J. Structural and Functional Properties of Platelet-Derived Growth Factor and Stem Cell Factor Receptors Cold Spring Harb. Perspect. Biol. 2013 5 a009100 10.1101/cshperspect.a009100 23906712 PMC3721287

107. Raica M. Cimpean A.M. Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy Pharmaceuticals 2010 3 572 599 10.3390/ph3030572 27713269 PMC4033970

108. Heldin C.H. Autocrine PDGF Stimulation in Malignancies Ups. J. Med. Sci. 2012 117 83 91 10.3109/03009734.2012.658119 22512244 PMC3339540

109. Hanahan D. Coussens L.M. Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment Cancer Cell 2012 21 309 322 10.1016/j.ccr.2012.02.022 22439926

110. Pietras K. Östman A. Hallmarks of Cancer: Interactions with the Tumor Stroma Exp. Cell Res. 2010 316 1324 1331 10.1016/j.yexcr.2010.02.045 20211171

111. Bataller R. Brenner D.A. Liver Fibrosis J. Clin. Investig. 2005 115 209 218 10.1172/JCI24282 15690074 PMC546435

112. Hernandez-Gea V. Friedman S.L. Pathogenesis of Liver Fibrosis Annu. Rev. Pathol. 2011 6 425 456 10.1146/annurev-pathol-011110-130246 21073339

113. Mogler C. König C. Wieland M. Runge A. Besemfelder E. Komljenovic D. Longerich T. Schirmacher P. Augustin H.G. Hepatic Stellate Cells Limit Hepatocellular Carcinoma Progression through the Orphan Receptor Endosialin EMBO Mol. Med. 2017 9 741 749 10.15252/emmm.201607222 28373218 PMC5452049

114. Zhao W. Zhang L. Xu Y. Zhang Z. Ren G. Tang K. Kuang P. Zhao B. Yin Z. Wang X. Hepatic Stellate Cells Promote Tumor Progression by Enhancement of Immunosuppressive Cells in an Orthotopic Liver Tumor Mouse Model Lab. Investig. 2014 94 182 191 10.1038/labinvest.2013.139 24296878

115. Xu Y. Zhao W. Xu J. Li J. Hong Z. Yin Z. Wang X. Activated Hepatic Stellate Cells Promote Liver Cancer by Induction of Myeloid-Derived Suppressor Cells through Cyclooxygenase-2 Oncotarget 2016 7 8866 8878 10.18632/oncotarget.6839 26758420 PMC4891010

116. Yu J.-H. Kim J.M. Kim J.K. Choi S.J. Lee K.S. Lee J.-W. Chang H.Y. Lee J. Il Platelet-Derived Growth Factor Receptor α in Hepatocellular Carcinoma Is a Prognostic Marker Independent of Underlying Liver Cirrhosis Oncotarget 2017 8 39534 39546 10.18632/oncotarget.17134 28465473 PMC5503630

117. Borkham-Kamphorst E. Herrmann J. Stoll D. Treptau J. Gressner A.M. Weiskirchen R. Dominant-Negative Soluble PDGF-Beta Receptor Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis Lab. Invest. 2004 84 766 777 10.1038/labinvest.3700094 15077122

118. Zhu K. Pan Q. Zhang X. Kong L.Q. Fan J. Dai Z. Wang L. Yang X.R. Hu J. Wan J.L. MiR-146a Enhances Angiogenic Activity of Endothelial Cells in Hepatocellular Carcinoma by Promoting PDGFRA Expression Carcinogenesis 2013 34 2071 2079 10.1093/carcin/bgt160 23671131

119. von Marschall Z. Scholz A. Cramer T. Schäfer G. Schirner M. Öberg K. Wiedenmann B. Höcker M. Rosewicz S. Effects of Interferon Alpha on Vascular Endothelial Growth Factor Gene Transcription and Tumor Angiogenesis J. Natl. Cancer Inst. 2003 95 437 448 10.1093/jnci/95.6.437 12644537

120. Ball S.G. Shuttleworth C.A. Kielty C.M. Vascular Endothelial Growth Factor Can Signal through Platelet-Derived Growth Factor Receptors J. Cell Biol. 2007 177 489 500 10.1083/jcb.200608093 17470632 PMC2064818

121. Zhang X.F. Tan X. Zeng G. Misse A. Singh S. Kim Y. Klaunig J.E. Monga S.P.S. Conditional Beta-Catenin Loss in Mice Promotes Chemical Hepatocarcinogenesis: Role of Oxidative Stress and Platelet-Derived Growth Factor Receptor Alpha/Phosphoinositide 3-Kinase Signaling Hepatology 2010 52 954 965 10.1002/hep.23747 20583210 PMC3100799

122. Awuah P.K. Rhieu B.H. Singh S. Misse A. Monga S.P.S. β-Catenin Loss in Hepatocytes Promotes Hepatocellular Cancer after Diethylnitrosamine and Phenobarbital Administration to Mice PLoS ONE 2012 7 e39771 10.1371/journal.pone.0039771 22761897 PMC3382575

123. Fischer A.N.M. Fuchs E. Mikula M. Huber H. Beug H. Mikulits W. PDGF Essentially Links TGF-Beta Signaling to Nuclear Beta-Catenin Accumulation in Hepatocellular Carcinoma Progression Oncogene 2007 26 3395 3405 10.1038/sj.onc.1210121 17130832

124. Zhou L. An N. Haydon R.C. Zhou Q. Cheng H. Peng Y. Jiang W. Luu H.H. Vanichakarn P. Szatkowski J.P. Tyrosine Kinase Inhibitor STI-571/Gleevec down-Regulates the β-Catenin Signaling Activity Cancer Lett. 2003 193 161 170 10.1016/S0304-3835(03)00013-2 12706873 PMC4527752

125. Kikuchi A. Monga S.P. PDGFRα in Liver Pathophysiology: Emerging Roles in Development, Regeneration, Fibrosis, and Cancer Gene Expr. 2015 16 109 127 10.3727/105221615X14181438356210 25700367 PMC4410163

126. Hernandez-Gea V. Toffanin S. Friedman S.L. Llovet J.M. Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma Gastroenterology 2013 144 512 527 10.1053/j.gastro.2013.01.002 23313965 PMC3578068

127. Wang Y. Liu D. Zhang T. Xia L. FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention Cancers 2021 13 1360 10.3390/cancers13061360 33802841 PMC8002748

128. Gauglhofer C. Sagmeister S. Schrottmaier W. Fischer C. Rodgarkia-Dara C. Mohr T. Stättner S. Bichler C. Kandioler D. Wrba F. Up-Regulation of the Fibroblast Growth Factor 8 Subfamily in Human Hepatocellular Carcinoma for Cell Survival and Neoangiogenesis Hepatology 2011 53 854 864 10.1002/hep.24099 21319186

129. Qiu W.-H. Zhou B.-S. Chu P.-G. Chen W.-G. Chung C. Shih J. Hwu P. Yeh C. Lopez R. Yen Y. Over-Expression of Fibroblast Growth Factor Receptor 3 in Human Hepatocellular Carcinoma World J. Gastroenterol. 2005 11 5266 5272 10.3748/wjg.v11.i34.5266 16149130 PMC4622793

130. Paur J. Nika L. Maier C. Moscu-Gregor A. Kostka J. Huber D. Mohr T. Heffeter P. Schrottmaier W.C. Kappel S. Fibroblast Growth Factor Receptor 3 Isoforms: Novel Therapeutic Targets for Hepatocellular Carcinoma? Hepatology 2015 62 1767 1778 10.1002/hep.28023 26235436

131. Raja A. Park I. Haq F. Ahn S.-M. FGF19-FGFR4 Signaling in Hepatocellular Carcinoma Cells 2019 8 536 10.3390/cells8060536 31167419 PMC6627123

132. Wang H. Yang J. Zhang K. Liu J. Li Y. Su W. Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and Its Pharmacotherapeutic Targets Front. Pharmacol. 2021 12 650388 10.3389/fphar.2021.650388 33935756 PMC8082422

133. Asada N. Tanaka Y. Hayashido Y. Toratani S. Kan M. Kitamoto M. Nakanishi T. Kajiyama G. Chayama K. Okamoto T. Expression of Fibroblast Growth Factor Receptor Genes in Human Hepatoma-Derived Cell Lines Vitr. Cell. Dev. Biol. Anim. 2003 39 321 328 10.1290/1543-706X(2003)039<0321:EOFGFR>2.0.CO;2 14753849

134. Sandhu D.S. Baichoo E. Roberts L.R. Fibroblast Growth Factor Signaling in Liver Carcinogenesis Hepatology 2014 59 1166 1173 10.1002/hep.26679 24716202

135. Cheng A.L. Shen Y.C. Zhu A.X. Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma Oncology 2011 81 372 380 10.1159/000335472 22269894

136. Poon R.T.P. Ng I.O.L. Lau C. Yu W.C. Fan S.T. Wong J. Correlation of Serum Basic Fibroblast Growth Factor Levels with Clinicopathologic Features and Postoperative Recurrence in Hepatocellular Carcinoma Am. J. Surg. 2001 182 298 304 10.1016/S0002-9610(01)00708-5 11587697

137. Midorikawa Y. Ishikawa S. Iwanari H. Imamura T. Sakamoto H. Miyazono K. Kodama T. Makuuchi M. Aburatani H. Glypican-3, Overexpressed in Hepatocellular Carcinoma, Modulates FGF2 and BMP-7 Signaling Int. J. Cancer 2003 103 455 465 10.1002/ijc.10856 12478660

138. Kim S.S. Eun J.W. Cho H.J. Lee H.Y. Seo C.W. Noh C.K. Shin S.J. Lee K.M. Cho S.W. Cheong J.Y. Effect of Fibroblast Growth Factor-2 and Its Receptor Gene Polymorphisms on the Survival of Patients with Hepatitis B Virus-Associated Hepatocellular Carcinoma Anticancer Res. 2019 39 2217 2226 10.21873/anticanres.13337 30952770

139. Pei Y. Sun X. Guo X. Yin H. Wang L. Tian F. Jing H. Liang X. Xu J. Shi P. FGF8 Promotes Cell Proliferation and Resistance to EGFR Inhibitors via Upregulation of EGFR in Human Hepatocellular Carcinoma Cells Oncol. Rep. 2017 38 2205 2210 10.3892/or.2017.5887 28791365

140. Ho H.K. Pok S. Streit S. Ruhe J.E. Hart S. Lim K.S. Loo H.L. Aung M.O. Lim S.G. Ullrich A. Fibroblast Growth Factor Receptor 4 Regulates Proliferation, Anti-Apoptosis and Alpha-Fetoprotein Secretion during Hepatocellular Carcinoma Progression and Represents a Potential Target for Therapeutic Intervention J. Hepatol. 2009 50 118 127 10.1016/j.jhep.2008.08.015 19008009

141. Yang H. Fang F. Chang R. Yang L. MicroRNA-140-5p Suppresses Tumor Growth and Metastasis by Targeting Transforming Growth Factor β Receptor 1 and Fibroblast Growth Factor 9 in Hepatocellular Carcinoma Hepatology 2013 58 205 217 10.1002/hep.26315 23401231

142. French D.M. Lin B.C. Wang M. Adams C. Shek T. Hötzel K. Bolon B. Ferrando R. Blackmore C. Schroeder K. Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models PLoS ONE 2012 7 e36713 10.1371/journal.pone.0036713 22615798 PMC3352934

143. Lin B.C. Desnoyers L.R. FGF19 and Cancer Adv. Exp. Med. Biol. 2012 728 183 194 10.1007/978-1-4614-0887-1_12 22396170

144. Liu W.Y. Xie D.M. Zhu G.Q. Huang G.Q. Lin Y.Q. Wang L.R. Shi K.Q. Hu B. Braddock M. Chen Y.P. Targeting Fibroblast Growth Factor 19 in Liver Disease: A Potential Biomarker and Therapeutic Target Expert Opin. Ther. Targets 2015 19 675 685 10.1517/14728222.2014.997711 25547779

145. Gu Q. Zhang B. Sun H. Xu Q. Tan Y. Wang G. Luo Q. Xu W. Yang S. Li J. Genomic Characterization of a Large Panel of Patient-Derived Hepatocellular Carcinoma Xenograft Tumor Models for Preclinical Development Oncotarget 2015 6 20160 20176 10.18632/oncotarget.3969 26062443 PMC4652995

146. Sheu M.J. Hsieh M.J. Chiang W.L. Yang S.F. Lee H.L. Lee L.M. Yeh C. Bin Fibroblast Growth Factor Receptor 4 Polymorphism Is Associated with Liver Cirrhosis in Hepatocarcinoma PLoS ONE 2015 10 e0122961 10.1371/journal.pone.0122961 25860955 PMC4393280

147. Lin Z.Z. Hsu C. Jeng Y.M. Hu F.C. Pan H.W. Wu Y.M. Hsu H.C. Cheng A.L. Klotho-Beta and Fibroblast Growth Factor 19 Expression Correlates with Early Recurrence of Resectable Hepatocellular Carcinoma Liver Int. 2019 39 1682 1691 10.1111/liv.14055 30698907

148. Naugler W.E. Tarlow B.D. Fedorov L.M. Taylor M. Pelz C. Li B. Darnell J. Grompe M. Fibroblast Growth Factor Signaling Controls Liver Size in Mice with Humanized Livers Gastroenterology 2015 149 728 740.e15 10.1053/j.gastro.2015.05.043 26028580 PMC4550566

149. Sawey E.T. Chanrion M. Cai C. Wu G. Zhang J. Zender L. Zhao A. Busuttil R.W. Yee H. Stein L. Identification of a Therapeutic Strategy Targeting Amplified FGF19 in Liver Cancer by Oncogenomic Screening Cancer Cell 2011 19 347 358 10.1016/j.ccr.2011.01.040 21397858 PMC3061399

150. Miura S. Mitsuhashi N. Shimizu H. Kimura F. Yoshidome H. Otsuka M. Kato A. Shida T. Okamura D. Miyazaki M. Fibroblast Growth Factor 19 Expression Correlates with Tumor Progression and Poorer Prognosis of Hepatocellular Carcinoma BMC Cancer 2012 12 56 10.1186/1471-2407-12-56 22309595 PMC3293719

151. Takahashi H. Shibuya M. The Vascular Endothelial Growth Factor (VEGF)/ VEGF Receptor System and Its Role under Physiological and Pathological Conditions Clin. Sci. 2005 109 227 241 10.1042/CS20040370 16104843

152. Apte R.S. Chen D.S. Ferrara N. Leading Edge Review VEGF in Signaling and Disease: Beyond Discovery and Development Cell 2019 176 1248 1264 10.1016/j.cell.2019.01.021 30849371 PMC6410740

153. Cannito S. Foglia B. Villano G. Turato C. Delgado T.C. Morello E. Pin F. Novo E. Napione L. Quarta S. SerpinB3 Differently Up-Regulates Hypoxia Inducible Factors-1α and -2α in Hepatocellular Carcinoma: Mechanisms Revealing Novel Potential Therapeutic Targets Cancers 2019 11 1933 10.3390/cancers11121933 31817100 PMC6966556

154. Germain S. Monnot C. Muller L. Eichmann A. Hypoxia-Driven Angiogenesis: Role of Tip Cells and Extracellular Matrix Scaffolding Curr. Opin. Hematol. 2010 17 245 251 10.1097/MOH.0b013e32833865b9 20308893

155. Nilsson M. Heymach J.V. Vascular Endothelial Growth Factor (VEGF) Pathway J. Thorac. Oncol. 2006 1 768 770 10.1097/01243894-200610000-00003 17409958

156. Kerbel R.S. Tumor Angiogenesis N. Engl. J. Med. 2008 358 2039 10.1056/NEJMra0706596 18463380 PMC4542009

157. Liu L. Qin S. Zheng Y. Han L. Zhang M. Luo N. Liu Z. Gu N. Gu X. Yin X. Molecular Targeting of VEGF/VEGFR Signaling by the Anti-VEGF Monoclonal Antibody BD0801 Inhibits the Growth and Induces Apoptosis of Human Hepatocellular Carcinoma Cells in Vitro and in Vivo Cancer Biol. Ther. 2017 18 166 176 10.1080/15384047.2017.1282019 28368741 PMC5389424

158. Ferrara N. Vascular Endothelial Growth Factor and Age-Related Macular Degeneration: From Basic Science to Therapy Nat. Med. 2010 16 1107 1111 10.1038/nm1010-1107 20930754

159. Jain R.K. Molecular Regulation of Vessel Maturation Nat. Med. 2003 9 685 693 10.1038/nm0603-685 12778167

160. Nagy J.A. Chang S.H. Dvorak A.M. Dvorak H.F. Why Are Tumour Blood Vessels Abnormal and Why Is It Important to Know? Br. J. Cancer 2009 100 865 869 10.1038/sj.bjc.6604929 19240721 PMC2661770

161. Ferrara N. Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev. 2004 25 581 611 10.1210/er.2003-0027 15294883

162. Tseng P.L. Tai M.H. Huang C.C. Wang C.C. Lin J.W. Hung C.H. Chen C.H. Wang J.H. Lu S.N. Lee C.M. Overexpression of VEGF Is Associated with Positive P53 Immunostaining in Hepatocellular Carcinoma (HCC) and Adverse Outcome of HCC Patients J. Surg. Oncol. 2008 98 349 357 10.1002/jso.21109 18646041

163. Zhang L. Wang J.N. Tang J.M. Kong X. Yang J.Y. Zheng F. Guo L.Y. Huang Y.Z. Zhang L. Tian L. VEGF Is Essential for the Growth and Migration of Human Hepatocellular Carcinoma Cells Mol. Biol. Rep. 2012 39 5085 5093 10.1007/s11033-011-1304-2 22161247 PMC4354771

164. Liu M. Yang S. Zhang D. Shui P. Song S. Yao J. Dai Y. Sun Q. Fructopyrano-(1→4)-Glucopyranose Inhibits the Proliferation of Liver Cancer Cells and Angiogenesis in a VEGF/VEGFR Dependent Manner Int. J. Clin. Exp. Med. 2014 7 3859 25550894 PMC4276152

165. Peng S. Wang Y. Peng H. Chen D. Shen S. Peng B. Chen M. Lencioni R. Kuang M. Autocrine Vascular Endothelial Growth Factor Signaling Promotes Cell Proliferation and Modulates Sorafenib Treatment Efficacy in Hepatocellular Carcinoma Hepatology 2014 60 1264 1277 10.1002/hep.27236 24849467

166. Mise M. Arii S. Higashituji H. Furutani M. Niwano M. Harada T. Ishigami S. Toda Y. Nakayama H. Fukumoto M. Clinical Significance of Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Gene Expression in Liver Tumor Hepatology 1996 23 455 464 10.1002/hep.510230309 8617424

167. Zhan P. Qian Q. Yu L.-K. Prognostic Significance of Vascular Endothelial Growth Factor Expression in Hepatocellular Carcinoma Tissue: A Meta-Analysis Hepatobiliary Surg. Nutr. 2013 2 148 10.3978/J.ISSN.2304-3881.2013.06.06 24570933 PMC3924673

168. Wang D. Luo L. Chen W. Chen L.Z. Zeng W.T. Li W. Huang X.H. Significance of the Vascular Endothelial Growth Factor and the Macrophage Migration Inhibitory Factor in the Progression of Hepatocellular Carcinoma Oncol. Rep. 2014 31 1199 1204 10.3892/or.2013.2946 24366206

169. Chinnasamy D. Yu Z. Theoret M.R. Zhao Y. Shrimali R.K. Morgan R.A. Feldman S.A. Restifo N.P. Rosenberg S.A. Gene Therapy Using Genetically Modified Lymphocytes Targeting VEGFR-2 Inhibits the Growth of Vascularized Syngenic Tumors in Mice J. Clin. Investig. 2010 120 3953 3968 10.1172/JCI43490 20978347 PMC2964987

170. Wang W. Ma Y. Li J. Shi H.S. Wang L.Q. Guo F.C. Zhang J. Li D. Mo B.H. Wen F. Specificity Redirection by CAR with Human VEGFR-1 Affinity Endows T Lymphocytes with Tumor-Killing Ability and Anti-Angiogenic Potency Gene Ther. 2013 20 970 978 10.1038/gt.2013.19 23636245

171. Hajari Taheri F. Hassani M. Sharifzadeh Z. Behdani M. Arashkia A. Abolhassani M. T Cell Engineered with a Novel Nanobody-Based Chimeric Antigen Receptor against VEGFR2 as a Candidate for Tumor Immunotherapy IUBMB Life 2019 71 1259 1267 10.1002/iub.2019 30724452

172. Xing H. Yang X. Xu Y. Tang K. Tian Z. Chen Z. Zhang Y. Xue Z. Rao Q. Wang M. Anti-Tumor Effects of Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Binding Domain-Modified Chimeric Antigen Receptor T Cells Cytotherapy 2021 23 810 819 10.1016/j.jcyt.2021.05.008 34244079

173. Akbari P. Katsarou A. Daghighian R. Van Mil L.W.H.G. Huijbers E.J.M. Griffioen A.W. Van Beijnum J.R. Directing CAR T Cells towards the Tumor Vasculature for the Treatment of Solid Tumors BBA Rev. Cancer 2022 1877 188701 10.1016/j.bbcan.2022.188701 35202772

174. Wang H. Rao B. Lou J. Li J. Liu Z. Li A. Cui G. Ren Z. Yu Z. The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma Front. Cell Dev. Biol. 2020 8 55 10.3389/fcell.2020.00055 32117981 PMC7018668

175. Nakamura T. Nawa K. Ichihara A. Partial Purification and Characterization of Hepatocyte Growth Factor from Serum of Hepatectomized Rats Biochem. Biophys. Res. Commun. 1984 122 1450 1459 10.1016/0006-291X(84)91253-1 6477569

176. Gherardi E. Stoker M. Hepatocytes and Scatter Factor Nature 1990 346 228 10.1038/346228b0 2142751

177. García-Vilas J.A. Medina M.Á. Updates on the Hepatocyte Growth Factor/c-Met Axis in Hepatocellular Carcinoma and Its Therapeutic Implications World J. Gastroenterol. 2018 24 3695 10.3748/wjg.v24.i33.3695 30197476 PMC6127652

178. Basilico C. Hultberg A. Blanchetot C. De Jonge N. Festjens E. Hanssens V. Osepa S.I. De Boeck G. Mira A. Cazzanti M. Four Individually Druggable MET Hotspots Mediate HGF-Driven Tumor Progression J. Clin. Investig. 2014 124 3172 3186 10.1172/JCI72316 24865428 PMC4071368

179. González M.N. de Mello W. Butler-Browne G.S. Silva-Barbosa S.D. Mouly V. Savino W. Riederer I. HGF Potentiates Extracellular Matrix-Driven Migration of Human Myoblasts: Involvement of Matrix Metalloproteinases and MAPK/ERK Pathway Skelet. Muscle 2017 7 20 10.1186/s13395-017-0138-6 29017538 PMC5635537

180. Pascale R.M. Feo F. Calvisi D.F. An Infernal Cross-Talk between Oncogenic β-Catenin and c-Met in Hepatocellular Carcinoma: Evidence from Mouse Modeling Hepatology 2016 64 1421 1423 10.1002/hep.28790 27596836

181. Scagliotti G.V. Novello S. von Pawel J. The Emerging Role of MET/HGF Inhibitors in Oncology Cancer Treat. Rev. 2013 39 793 801 10.1016/j.ctrv.2013.02.001 23453860

182. Zhang Y.S. Chu J.H. Cui S.X. Song Z.Y. Qu X.J. Des-γ-Carboxy Prothrombin (DCP) as a Potential Autologous Growth Factor for the Development of Hepatocellular Carcinoma Cell. Physiol. Biochem. 2014 34 903 915 10.1159/000366308 25200250

183. Bozkaya G. Korhan P. Çokakli M. Erdal E. Saǧol Ö. Karademir S. Korch C. Atabey N. Cooperative Interaction of MUC1 with the HGF/c-Met Pathway during Hepatocarcinogenesis Mol. Cancer 2012 11 64 10.1186/1476-4598-11-64 22962849 PMC3542123

184. Tao J. Xu E. Zhao Y. Singh S. Li X. Couchy G. Chen X. Zucman-Rossi J. Chikina M. Monga S.P.S. Modeling a Human Hepatocellular Carcinoma Subset in Mice through Coexpression of Met and Point-Mutant β-Catenin Hepatology 2016 64 1587 1605 10.1002/hep.28601 27097116 PMC5073058

185. Corso S. Giordano S. Cell-Autonomous and Non-Cell-Autonomous Mechanisms of HGF/MET-Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective Cancer Discov. 2013 3 978 992 10.1158/2159-8290.CD-13-0040 23901039

186. Bouattour M. Raymond E. Qin S. Cheng A.L. Stammberger U. Locatelli G. Faivre S. Recent Developments of C-Met as a Therapeutic Target in Hepatocellular Carcinoma Hepatology 2018 67 1132 1149 10.1002/hep.29496 28862760 PMC5873445

187. Zhang S.Z. Pan F.Y. Xu J.F. Yuan J. Guo S.Y. Dai G. Xue B. Shen W.G. Wen C.J. Zhao D.H. Knockdown of C-Met by Adenovirus-Delivered Small Interfering RNA Inhibits Hepatocellular Carcinoma Growth in Vitro and in Vivo Mol. Cancer Ther. 2005 4 1577 1584 10.1158/1535-7163.MCT-05-0106 16227408

188. Wang S.W. Pan S.L. Peng C.Y. Huang D.Y. Tsai A.C. Chang Y.L. Guh J.H. Kuo S.C. Lee K.H. Teng C.M. CHM-1 Inhibits Hepatocyte Growth Factor-Induced Invasion of SK-Hep-1 Human Hepatocellular Carcinoma Cells by Suppressing Matrix Metalloproteinase-9 Expression Cancer Lett. 2007 257 87 96 10.1016/j.canlet.2007.07.002 17689859

189. Ding W. You H. Dang H. LeBlanc F. Galicia V. Lu S.C. Stiles B. Rountree C.B. Epithelial-to-Mesenchymal Transition of Murine Liver Tumor Cells Promotes Invasion Hepatology 2010 52 945 953 10.1002/hep.23748 20564331 PMC3032356

190. He M. Peng A. Huang X.Z. Shi D.C. Wang J.C. Zhao Q. Lin H. Kuang D.M. Ke P.F. Lao X.M. Peritumoral Stromal Neutrophils Are Essential for C-Met-Elicited Metastasis in Human Hepatocellular Carcinoma Oncoimmunology 2016 5 e1219828 10.1080/2162402X.2016.1219828 27853643 PMC5087290

191. Jia C.C. Wang T.T. Liu W. Fu B.S. Hua X.F. Wang G.Y. Li T.J. Li X. Wu X.Y. Tai Y. Cancer-Associated Fibroblasts from Hepatocellular Carcinoma Promote Malignant Cell Proliferation by HGF Secretion PLoS ONE 2013 8 e63243 10.1371/journal.pone.0063243 23667593 PMC3647063

192. Karabulut S. Tas F. Akyüz F. Ormeci A.C. Serilmez M. Soydinç H.O. Vatansever S. Yasasever V. Clinical Significance of Serum Hepatocyte Growth Factor (HGF) Levels in Hepatocellular Carcinoma Tumor Biol. 2014 35 2327 2333 10.1007/s13277-013-1308-8 24142532

193. Unić A. Derek L. Duvnjak M. Patrlj L. Rakić M. Kujundžić M. Renjić V. Štoković N. Dinjar P. Jukic A. Diagnostic Specificity and Sensitivity of PIVKAII, GP3, CSTB, SCCA1 and HGF for the Diagnosis of Hepatocellular Carcinoma in Patients with Alcoholic Liver Cirrhosis Ann. Clin. Biochem. 2018 55 355 362 10.1177/0004563217726808 28766361

194. You H. Ding W. Dang H. Jiang Y. Rountree C.B. C-Met Represents a Potential Therapeutic Target for Personalized Treatment in Hepatocellular Carcinoma Hepatology 2011 54 879 889 10.1002/hep.24450 21618573 PMC3181384

195. Du Z. Caenepeel S. Shen Y. Rex K. Zhang Y. He Y. Tang E.T. Wang O. Zhong W. Zhou H. Preclinical Evaluation of AMG 337, a Highly Selective Small Molecule MET Inhibitor, in Hepatocellular Carcinoma Mol. Cancer Ther. 2016 15 1227 1237 10.1158/1535-7163.MCT-15-0745 27196749

196. Luo T. Zhang S.G. Zhu L.F. Zhang F.X. Li W. Zhao K. Wen X.X. Yu M. Zhan Y.Q. Chen H. A Selective C-Met and Trks Inhibitor Indo5 Suppresses Hepatocellular Carcinoma Growth J. Exp. Clin. Cancer Res. 2019 38 130 10.1186/s13046-019-1104-4 30885237 PMC6421704

197. Goyal L. Muzumdar M.D. Zhu A.X. Targeting the HGF/c-MET Pathway in Hepatocellular Carcinoma Clin. Cancer Res. 2013 19 2310 2318 10.1158/1078-0432.CCR-12-2791 23388504 PMC4583193

198. Santoro A. Rimassa L. Borbath I. Daniele B. Salvagni S. Van Laethem J.L. Van Vlierberghe H. Trojan J. Kolligs F.T. Weiss A. Tivantinib for Second-Line Treatment of Advanced Hepatocellular Carcinoma: A Randomised, Placebo-Controlled Phase 2 Study Lancet. Oncol. 2013 14 55 63 10.1016/S1470-2045(12)70490-4 23182627

199. Liu J.J. Li Y. Chen W.S. Liang Y. Wang G. Zong M. Kaneko K. Xu R. Karin M. Feng G.S. Shp2 Deletion in Hepatocytes Suppresses Hepatocarcinogenesis Driven by Oncogenic β-Catenin, PIK3CA and MET J. Hepatol. 2018 69 79 88 10.1016/j.jhep.2018.02.014 29505847 PMC6008184

200. Karagonlar Z.F. Korhan P. Atabey N. Targeting C-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma Drug Dev. Res. 2015 76 357 367 10.1002/ddr.21274 26363180

201. Cai H. Zhou H. Miao Y. Li N. Zhao L. Jia L. MiRNA Expression Profiles Reveal the Involvement of MiR-26a, MiR-548l and MiR-34a in Hepatocellular Carcinoma Progression through Regulation of ST3GAL5 Lab. Invest. 2017 97 530 542 10.1038/labinvest.2017.12 28218742

202. Wu H. Tao J. Li X. Zhang T. Zhao L. Wang Y. Zhang L. Xiong J. Zeng Z. Zhan N. MicroRNA-206 Prevents the Pathogenesis of Hepatocellular Carcinoma by Modulating Expression of Met Proto-Oncogene and Cyclin-Dependent Kinase 6 in Mice Hepatology 2017 66 1952 1967 10.1002/hep.29374 28714063 PMC5696004

203. Yan S. Shan X. Chen K. Liu Y. Yu G. Chen Q. Zeng T. Zhu L. Dang H. Chen F. LINC00052/MiR-101-3p Axis Inhibits Cell Proliferation and Metastasis by Targeting SOX9 in Hepatocellular Carcinoma Gene 2018 679 138 149 10.1016/j.gene.2018.08.038 30098428

204. Xue X. Wang X. Zhao Y. Hu R. Qin L. Exosomal MiR-93 Promotes Proliferation and Invasion in Hepatocellular Carcinoma by Directly Inhibiting TIMP2/TP53INP1/CDKN1A Biochem. Biophys. Res. Commun. 2018 502 515 521 10.1016/j.bbrc.2018.05.208 29859935

205. Liu Y. Tan J. Ou S. Chen J. Chen L. MicroRNA-101-3p Suppresses Proliferation and Migration in Hepatocellular Carcinoma by Targeting the HGF/c-Met Pathway Investig. New Drugs 2020 38 60 69 10.1007/s10637-019-00766-8 30929159

206. Guizhen Z. Guanchang J. Liwen L. Huifen W. Zhigang R. Ranran S. Zujiang Y. The Tumor Microenvironment of Hepatocellular Carcinoma and Its Targeting Strategy by CAR-T Cell Immunotherapy Front. Endocrinol. 2022 13 918869 10.3389/fendo.2022.918869 PMC9452721 36093115

207. Tchou J. Zhao Y. Levine B.L. Zhang P.J. Davis M.M. Melenhorst J.J. Kulikovskaya I. Brennan A.L. Liu X. Lacey S.F. Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer Cancer Immunol. Res. 2017 5 1152 1161 10.1158/2326-6066.CIR-17-0189 29109077 PMC5712264

208. Mori J. Adachi K. Sakoda Y. Sasaki T. Goto S. Matsumoto H. Nagashima Y. Matsuyama H. Tamada K. Anti-tumor Efficacy of Human Anti-c-met CAR-T Cells against Papillary Renal Cell Carcinoma in an Orthotopic Model Cancer Sci. 2021 112 1417 10.1111/cas.14835 33539630 PMC8019206

209. Kang C.H. Kim Y. Lee D.Y. Choi S.U. Lee H.K. Park C.H. C-Met-Specific Chimeric Antigen Receptor T Cells Demonstrate Anti-Tumor Effect in c-Met Positive Gastric Cancer Cancers 2021 13 5738 10.3390/cancers13225738 34830894 PMC8616279

210. Liu L. Liu B. Yu J. Zhang D. Shi J. Liang P. Development of a Toll-Like Receptor-Based Gene Signature That Can Predict Prognosis, Tumor Microenvironment, and Chemotherapy Response for Hepatocellular Carcinoma Front. Mol. Biosci. 2021 8 729789 10.3389/fmolb.2021.729789 34621787 PMC8490642

211. Soares J.B. Pimentel-Nunes P. Afonso L. Rolanda C. Lopes P. Roncon-Albuquerque R. Gonçalves N. Boal-Carvalho I. Pardal F. Lopes S. Increased Hepatic Expression of TLR2 and TLR4 in the Hepatic Inflammation-Fibrosis-Carcinoma Sequence Innate Immun. 2012 18 700 708 10.1177/1753425912436762 22330637

212. Akira S. Takeda K. Toll-like Receptor Signalling Nat. Rev. Immunol. 2004 4 499 511 10.1038/nri1391 15229469

213. Fukata M. Chen A. Klepper A. Krishnareddy S. Vamadevan A.S. Thomas L.S. Xu R. Inoue H. Arditi M. Dannenberg A.J. Cox-2 Is Regulated by Toll-like Receptor-4 (TLR4) Signaling: Role in Proliferation and Apoptosis in the Intestine Gastroenterology 2006 131 862 877 10.1053/j.gastro.2006.06.017 16952555 PMC2169292

214. Spitzer J.A. Zheng M. Kolls J.K. Vande Stouwe C. Spitzer J.J. Ethanol and LPS Modulate NF-KappaB Activation, Inducible NO Synthase and COX-2 Gene Expression in Rat Liver Cells in Vivo Front. Biosci. 2002 7 a99 a108 10.2741/spitzer 11994208

215. Lee I.T. Lee C.W. Tung W.H. Wang S.W. Lin C.C. Shu J.C. Yang C.M. Cooperation of TLR2 with MyD88, PI3K, and Rac1 in Lipoteichoic Acid-Induced CPLA2/COX-2-Dependent Airway Inflammatory Responses Am. J. Pathol. 2010 176 1671 1684 10.2353/ajpath.2010.090714 20167866 PMC2843459

216. Szabo G. Dolganiuc A. Mandrekar P. Pattern Recognition Receptors: A Contemporary View on Liver Diseases Hepatology 2006 44 287 298 10.1002/hep.21308 16871558

217. Gao B. Jeong W.-I. Tian Z. Liver: An Organ with Predominant Innate Immunity Hepatology 2008 47 729 736 10.1002/hep.22034 18167066

218. Roh Y.S. Zhang B. Loomba R. Seki E. TLR2 and TLR9 Contribute to Alcohol-Mediated Liver Injury through Induction of CXCL1 and Neutrophil Infiltration Am. J. Physiol. Gastrointest. Liver Physiol. 2015 309 30 41 10.1152/ajpgi.00031.2015 PMC4491507 25930080

219. Li S. Sun R. Chen Y. Wei H. Tian Z. TLR2 Limits Development of Hepatocellular Carcinoma by Reducing IL18-Mediated Immunosuppression Cancer Res. 2015 75 986 995 10.1158/0008-5472.CAN-14-2371 25600646

220. Huang Y. Cai B. Xu M. Qiu Z. Tao Y. Zhang Y. Wang J. Xu Y. Zhou Y. Yang J. Gene Silencing of Toll-like Receptor 2 Inhibits Proliferation of Human Liver Cancer Cells and Secretion of Inflammatory Cytokines PLoS ONE 2012 7 e38890 10.1371/journal.pone.0038890 22815694 PMC3398009

221. Nischalke H.D. Coenen M. Berger C. Aldenhoff K. Müller T. Berg T. Krämer B. Körner C. Odenthal M. Schulze F. The Toll-like Receptor 2 (TLR2) -196 to -174 Del/Ins Polymorphism Affects Viral Loads and Susceptibility to Hepatocellular Carcinoma in Chronic Hepatitis C Int. J. Cancer 2012 130 1470 1475 10.1002/ijc.26143 21500195

222. Mohamed F.E.Z.A. Hammad S. Luong T.V. Dewidar B. Al-Jehani R. Davies N. Dooley S. Jalan R. Expression of TLR-2 in Hepatocellular Carcinoma Is Associated with Tumour Proliferation, Angiogenesis and Caspase-3 Expression Pathol. Res. Pract. 2020 216 152980 10.1016/j.prp.2020.152980 32703481

223. Rakoff-Nahoum S. Medzhitov R. Toll-like Receptors and Cancer Nat. Rev. Cancer 2009 9 57 63 10.1038/nrc2541 19052556

224. Chen R. Alvero A.B. Silasi D.A. Steffensen K.D. Mor G. Cancers Take Their Toll--the Function and Regulation of Toll-like Receptors in Cancer Cells Oncogene 2008 27 225 233 10.1038/sj.onc.1210907 18176604

225. Pimentel-Nunes P. Soares J.B. Roncon-Albuquerque R. Dinis-Ribeiro M. Leite-Moreira A.F. Toll-like Receptors as Therapeutic Targets in Gastrointestinal Diseases Expert Opin. Ther. Targets 2010 14 347 368 10.1517/14728221003642027 20146632

226. Eiró N. Altadill A. Juárez L.M. Rodríguez M. González L.O. Atienza S. Bermúdez S. Fernandez-Garcia B. Fresno-Forcelledo M.F. Rodrigo L. Toll-like Receptors 3, 4 and 9 in Hepatocellular Carcinoma: Relationship with Clinicopathological Characteristics and Prognosis Hepatol. Res. 2014 44 769 778 10.1111/hepr.12180 23742263

227. Wang Z. Lin H. Hua F. Hu Z.W. Repairing DNA Damage by XRCC6/KU70 Reverses TLR4-Deficiency-Worsened HCC Development via Restoring Senescence and Autophagic Flux Autophagy 2013 9 925 927 10.4161/auto.24229 23518600 PMC3672303

228. Papadakos S.P. Arvanitakis K. Stergiou I.E. Lekakis V. Davakis S. Christodoulou M.I. Germanidis G. Theocharis S. The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks? Cancers 2023 15 2795 10.3390/cancers15102795 37345131 PMC10216531

229. Yang J. Zhang J.X. Wang H. Wang G.L. Hu Q.G. Zheng Q.C. Hepatocellular Carcinoma and Macrophage Interaction Induced Tumor Immunosuppression via Treg Requires TLR4 Signaling World J. Gastroenterol. 2012 18 2938 2947 10.3748/wjg.v18.i23.2938 22736917 PMC3380321

230. Zhang J. Zhang Q. Lou Y. Fu Q. Chen Q. Wei T. Yang J. Tang J. Wang J. Chen Y. Hypoxia-Inducible Factor-1α/Interleukin-1β Signaling Enhances Hepatoma Epithelial-Mesenchymal Transition through Macrophages in a Hypoxic-Inflammatory Microenvironment Hepatology 2018 67 1872 1889 10.1002/hep.29681 29171040

231. Zhou S. Du R. Wang Z. Shen W. Gao R. Jiang S. Fang Y. Shi Y. Chang A. Liu L. TLR4 Increases the Stemness and Is Highly Expressed in Relapsed Human Hepatocellular Carcinoma Cancer Med. 2019 8 2325 2337 10.1002/cam4.2070 30957973 PMC6536932

232. Zhang C. Wang N. Tan H.Y. Guo W. Chen F. Zhong Z. Man K. Tsao S.W. Lao L. Feng Y. Direct Inhibition of the TLR4/MyD88 Pathway by Geniposide Suppresses HIF-1α-Independent VEGF Expression and Angiogenesis in Hepatocellular Carcinoma Br. J. Pharmacol. 2020 177 3240 3257 10.1111/bph.15046 32144747 PMC7312435

233. Zlotnik A. Yoshie O. The Chemokine Superfamily Revisited Immunity 2012 36 705 716 10.1016/j.immuni.2012.05.008 22633458 PMC3396424

234. Molon B. Gri G. Bettella M. Gómez-Moutón C. Lanzavecchia A. Martínez-A C. Mañes S. Viola A. T Cell Costimulation by Chemokine Receptors Nat. Immunol. 2005 6 465 471 10.1038/ni1191 15821738

235. Kim J.W. Ferris R.L. Whiteside T.L. Chemokine C Receptor 7 Expression and Protection of Circulating CD8+ T Lymphocytes from Apoptosis Clin. Cancer Res. 2005 11 7901 7910 10.1158/1078-0432.CCR-05-1346 16278415

236. Coghill J.M. Fowler K.A. West M.L. Fulton L.S.M. Van Deventer H. McKinnon K.P. Vincent B.G. Lin K. Panoskaltsis-Mortari A. Cook D.N. CC Chemokine Receptor 8 Potentiates Donor Treg Survival and Is Critical for the Prevention of Murine Graft-versus-Host Disease Blood 2013 122 825 836 10.1182/blood-2012-06-435735 23798714 PMC3731935

237. Zhang Z. Mao M. Wang F. Zhang Y. Shi J. Chang L. Wu X. Zhang Z. Xu P. Lu S. Comprehensive Analysis and Immune Landscape of Chemokines- and Chemokine Receptors-Based Signature in Hepatocellular Carcinoma Front. Immunol. 2023 14 1164669 10.3389/fimmu.2023.1164669 37545521 PMC10399597

238. Shibuta K. Mori M. Shimoda K. Inoue H. Mitra P. Barnard G.F. Regional Expression of CXCL12/CXCR4 in Liver and Hepatocellular Carcinoma and Cell-Cycle Variation during in Vitro Differentiation Jpn. J. Cancer Res. 2002 93 789 797 10.1111/j.1349-7006.2002.tb01321.x 12149145 PMC5927066

239. Zheng K. Li H.-Y. Su X.-L. Wang X.-Y. Tian T. Li F. Ren G.-S. Chemokine Receptor CXCR7 Regulates the Invasion, Angiogenesis and Tumor Growth of Human Hepatocellular Carcinoma Cells J. Exp. Clin. Cancer Res. 2010 29 31 10.1186/1756-9966-29-31 20380740 PMC2859378

240. Monnier J. Boissan M. L’Helgoualc’H A. Lacombe M.L. Turlin B. Zucman-Rossi J. Théret N. Piquet-Pellorce C. Samson M. CXCR7 Is Up-Regulated in Human and Murine Hepatocellular Carcinoma and Is Specifically Expressed by Endothelial Cells Eur. J. Cancer 2012 48 138 148 10.1016/j.ejca.2011.06.044 21778049

241. Kaemmerer D. Schindler R. Mußbach F. Dahmen U. Altendorf-Hofmann A. Dirsch O. Sänger J. Schulz S. Lupp A. Somatostatin and CXCR4 Chemokine Receptor Expression in Hepatocellular and Cholangiocellular Carcinomas: Tumor Capillaries as Promising Targets BMC Cancer 2017 17 896 10.1186/s12885-017-3911-3 29282035 PMC5745780

242. Liu H. Pan Z. Li A. Fu S. Lei Y. Sun H. Wu M. Zhou W. Roles of Chemokine Receptor 4 (CXCR4) and Chemokine Ligand 12 (CXCL12) in Metastasis of Hepatocellular Carcinoma Cells Cell. Mol. Immunol. 2008 5 373 378 10.1038/cmi.2008.46 18954561 PMC4073694

243. Bertran E. Crosas-Molist E. Sancho P. Caja L. Lopez-Luque J. Navarro E. Egea G. Lastra R. Serrano T. Ramos E. Overactivation of the TGF-β Pathway Confers a Mesenchymal-like Phenotype and CXCR4-Dependent Migratory Properties to Liver Tumor Cells Hepatology 2013 58 2032 2044 10.1002/hep.26597 23813475

244. Zhang R. Pan X. Huang Z. Weber G.F. Zhang G. Osteopontin Enhances the Expression and Activity of MMP-2 via the SDF-1/CXCR4 Axis in Hepatocellular Carcinoma Cell Lines PLoS ONE 2011 6 e23831 10.1371/journal.pone.0023831 21909361 PMC3166084

245. Zhou Z. Deng H. Yan W. Luo M. Tu W. Xia Y. He J. Han P. Fu Y. Tian D. AEG-1 Promotes Anoikis Resistance and Orientation Chemotaxis in Hepatocellular Carcinoma Cells PLoS ONE 2014 9 e100372 10.1371/journal.pone.0100372 24941119 PMC4062488

246. Jahanban-Esfahlan R. de la Guardia M. Ahmadi D. Yousefi B. Modulating Tumor Hypoxia by Nanomedicine for Effective Cancer Therapy J. Cell. Physiol. 2018 233 2019 2031 10.1002/jcp.25859 28198007

247. Deol A. Abrams J. Masood A. Al-Kadhimi Z. Abidi M.H. Ayash L. Lum L.G. Ratanatharathorn V. Uberti J.P. Long-Term Follow up of Patients Proceeding to Transplant Using Plerixafor Mobilized Stem Cells and Incidence of Secondary Myelodysplastic Syndrome/AML Bone Marrow Transpl. 2013 48 1112 1116 10.1038/bmt.2013.10 23474805 PMC3773813

248. Hirano S. Iwashita Y. Sasaki A. Kai S. Ohta M. Kitano S. Increased MRNA Expression of Chemokines in Hepatocellular Carcinoma with Tumor-Infiltrating Lymphocytes J. Gastroenterol. Hepatol. 2007 22 690 696 10.1111/j.1440-1746.2006.04551.x 17444857

249. Liu Z. Yang L. Xu J. Zhang X. Wang B. Enhanced Expression and Clinical Significance of Chemokine Receptor CXCR2 in Hepatocellular Carcinoma J. Surg. Res. 2011 166 241 246 10.1016/j.jss.2009.07.014 20018298

250. Zhou S.L. Zhou Z.J. Hu Z.Q. Li X. Huang X.W. Wang Z. Fan J. Dai Z. Zhou J. CXCR2/CXCL5 Axis Contributes to Epithelial-Mesenchymal Transition of HCC Cells through Activating PI3K/Akt/GSK-3β/Snail Signaling Cancer Lett. 2015 358 124 135 10.1016/j.canlet.2014.11.044 25462858

251. Gao Q. Zhao Y.J. Wang X.Y. Qiu S.J. Shi Y.H. Sun J. Yi Y. Shi J.Y. Shi G.M. Ding Z.-B. CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma Cancer Res. 2012 72 3546 3556 10.1158/0008-5472.CAN-11-4032 22710437

252. Yeh C.-B. Tsai H.T. Chen Y.C. Kuo W.H. Chen T.Y. Hsieh Y.H. Chou M.C. Yang S.F. Genetic Polymorphism of CCR2-64I Increased the Susceptibility of Hepatocellular Carcinoma J. Surg. Oncol. 2010 102 264 270 10.1002/jso.21623 20740585

253. Qin C.J. Zhao L.H. Zhou X. Zhang H.L. Wen W. Tang L. Zeng M. Wang M.-D. Fu G.B. Huang S. Inhibition of Dipeptidyl Peptidase IV Prevents High Fat Diet-Induced Liver Cancer Angiogenesis by Downregulating Chemokine Ligand 2 Cancer Lett. 2018 420 26 37 10.1016/j.canlet.2018.01.064 29409972

254. Nahon P. Sutton A. Rufat P. Simon C. Trinchet J.C. Gattegno L. Beaugrand M. Charnaux N. Chemokine System Polymorphisms, Survival and Hepatocellular Carcinoma Occurrence in Patients with Hepatitis C Virus-Related Cirrhosis World J. Gastroenterol. 2008 14 713 719 10.3748/wjg.14.713 18205260 PMC2683997

255. Ochoa-Callejero L. Pérez-Martínez L. Rubio-Mediavilla S. Oteo J.A. Martínez A. Blanco J.R. Maraviroc, a CCR5 Antagonist, Prevents Development of Hepatocellular Carcinoma in a Mouse Model PLoS ONE 2013 8 e53992 10.1371/journal.pone.0053992 23326556 PMC3541191

256. Wu Q. Chen J.X. Chen Y. Cai L.L. Wang X.Z. Guo W.H. Zheng J.F. The Chemokine Receptor CCR10 Promotes Inflammation-Driven Hepatocarcinogenesis via PI3K/Akt Pathway Activation Cell Death Dis. 2018 9 232 10.1038/s41419-018-0267-9 29445190 PMC5833857

257. Du D. Liu Y. Qian H. Zhang B. Tang X. Zhang T. Liu W. The Effects of the CCR6/CCL20 Biological Axis on the Invasion and Metastasis of Hepatocellular Carcinoma Int. J. Mol. Sci. 2014 15 6441 6452 10.3390/ijms15046441 24743888 PMC4013639

258. Hippe A. Braun S.A. Oláh P. Gerber P.A. Schorr A. Seeliger S. Holtz S. Jannasch K. Pivarcsi A. Buhren B. EGFR/Ras-Induced CCL20 Production Modulates the Tumour Microenvironment Br. J. Cancer 2020 123 942 954 10.1038/s41416-020-0943-2 32601464 PMC7493992

259. Wei Z. Liu H.T. MAPK Signal Pathways in the Regulation of Cell Proliferation in Mammalian Cells Cell Res. 2002 12 9 18 10.1038/SJ.CR.7290105 11942415

260. Guo Y. Pan W. Liu S. Shen Z. Xu Y. Hu L. ERK/MAPK Signalling Pathway and Tumorigenesis Exp. Ther. Med. 2020 19 1997 2007 10.3892/etm.2020.8454 32104259 PMC7027163

261. Pudewell S. Wittich C. Kazemein Jasemi N.S. Bazgir F. Ahmadian M.R. Accessory Proteins of the RAS-MAPK Pathway: Moving from the Side Line to the Front Line Commun. Biol. 2021 4 696 10.1038/s42003-021-02149-3 34103645 PMC8187363

262. Burotto M. Chiou V.L. Lee J.M. Kohn E.C. The MAPK Pathway across Different Malignancies: A New Perspective Cancer 2014 120 3446 10.1002/cncr.28864 24948110 PMC4221543

263. Campbell P.J. Getz G. Korbel J.O. Stuart J.M. Jennings J.L. Stein L.D. Perry M.D. Nahal-Bose H.K. Ouellette B.F.F. Li C.H. Pan-Cancer Analysis of Whole Genomes Nature 2020 578 82 93 10.1038/S41586-020-1969-6 32025007 PMC7025898

264. Campbell B.B. Galati M.A. Stone S.C. Riemenschneider A.N. Edwards M. Sudhaman S. Siddaway R. Komosa M. Nunes N.M. Nobre L. Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition Cancer Discov. 2021 11 1454 1467 10.1158/2159-8290.CD-20-1050 33563663 PMC8406556

265. Delire B. Stärkel P. The Ras/MAPK Pathway and Hepatocarcinoma: Pathogenesis and Therapeutic Implications Eur. J. Clin. Investig. 2015 45 609 623 10.1111/eci.12441 25832714

266. Roberts L.R. Gores G.J. Hepatocellular Carcinoma: Molecular Pathways and New Therapeutic Targets Semin. Liver Dis. 2005 25 212 225 10.1055/s-2005-871200 15918149

267. McCubrey J.A. Steelman L.S. Chappell W.H. Abrams S.L. Wong E.W.T. Chang F. Lehmann B. Terrian D.M. Milella M. Tafuri A. Roles of the Raf/MEK/ERK Pathway in Cell Growth, Malignant Transformation and Drug Resistance Biochim. Biophys. Acta Mol. Cell Res. 2007 1773 1263 1284 10.1016/j.bbamcr.2006.10.001 17126425 PMC2696318

268. Chen L. Shi Y. Jiang C.Y. Wei L.X. Wang Y.L. Dai G.H. Expression and Prognostic Role of Pan-Ras, Raf-1, PMEK1 and PERK1/2 in Patients with Hepatocellular Carcinoma Eur. J. Surg. Oncol. 2011 37 513 520 10.1016/j.ejso.2011.01.023 21324414

269. O’Neil B.H. Goff L.W. Kauh J.S.W. Strosberg J.R. Bekaii-Saab T.S. Lee R.M. Kazi A. Moore D.T. Learoyd M. Lush R.M. Phase II Study of the Mitogen-Activated Protein Kinase 1/2 Inhibitor Selumetinib in Patients with Advanced Hepatocellular Carcinoma J. Clin. Oncol. 2011 29 2350 2356 10.1200/JCO.2010.33.9432 21519015 PMC3107750

270. Kim R. Tan E. Wang E. Mahipal A. Chen D.-T. Cao B. Masawi F. Machado C. Yu J. Kim D.W. A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer Oncologist 2020 25 e1893 e1899 10.1634/theoncologist.2020-0759 32776632 PMC8186409

271. Harrison D.A. The JAK/STAT Pathway Cold Spring Harb. Perspect. Biol. 2012 4 a011205 10.1101/cshperspect.a011205 22383755 PMC3282412

272. Schindler C. Levy D.E. Decker T. JAK-STAT Signaling: From Interferons to Cytokines J. Biol. Chem. 2007 282 20059 20063 10.1074/jbc.R700016200 17502367

273. Hu X. li J. Fu M. Zhao X. Wang W. The JAK/STAT Signaling Pathway: From Bench to Clinic Signal Transduct. Target. Ther. 2021 6 402 10.1038/s41392-021-00791-1 34824210 PMC8617206

274. Jang Y.-N. Baik E.J. JAK-STAT Pathway and Myogenic Differentiation JAK-STAT 2013 2 e23282 10.4161/jkst.23282 24058805 PMC3710318

275. Herrera S.C. Bach E.A. JAK/STAT Signaling in Stem Cells and Regeneration: From Drosophila to Vertebrates Development 2019 146 dev167643 10.1242/dev.167643 30696713 PMC6361132

276. Al Zaid Siddiquee K. Turkson J. STAT3 as a Target for Inducing Apoptosis in Solid and Hematological Tumors Cell Res. 2008 18 254 10.1038/cr.2008.18 18227858 PMC2610254

277. Banerjee S. Biehl A. Gadina M. Hasni S. Schwartz D.M. JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects Drugs 2017 77 521 10.1007/s40265-017-0701-9 28255960 PMC7102286

278. Gurzov E.N. Stanley W.J. Pappas E.G. Thomas H.E. Gough D.J. The JAK/STAT Pathway in Obesity and Diabetes FEBS J. 2016 283 3002 3015 10.1111/febs.13709 26972840

279. Lokau J. Garbers C. Activating Mutations of the Gp130/JAK/STAT Pathway in Human Diseases Adv. Protein Chem. Struct. Biol. 2019 116 283 309 10.1016/BS.APCSB.2018.11.007 31036294

280. Shahmarvand N. Nagy A. Shahryari J. Ohgami R.S. Mutations in the Signal Transducer and Activator of Transcription Family of Genes in Cancer Cancer Sci. 2018 109 926 10.1111/cas.13525 29417693 PMC5891179

281. Hornakova T. Springuel L. Devreux J. Dusa A. Constantinescu S.N. Knoops L. Renauld J.C. Oncogenic JAK1 and JAK2-Activating Mutations Resistant to ATP-Competitive Inhibitors Haematologica 2011 96 845 853 10.3324/haematol.2010.036350 21393331 PMC3105646

282. Brooks A.J. Putoczki T. JAK-STAT Signalling Pathway in Cancer Cancers 2020 12 1971 10.3390/cancers12071971 32698360 PMC7409105

283. Kan Z. Zheng H. Liu X. Li S. Barber T.D. Gong Z. Gao H. Hao K. Willard M.D. Xu J. Whole-Genome Sequencing Identifies Recurrent Mutations in Hepatocellular Carcinoma Genome Res. 2013 23 1422 1433 10.1101/gr.154492.113 23788652 PMC3759719

284. Dhillon S. Tofacitinib: A Review in Rheumatoid Arthritis Drugs 2017 77 1987 2001 10.1007/s40265-017-0835-9 29139090

285. Al-Salama Z.T. Scott L.J. Baricitinib: A Review in Rheumatoid Arthritis Drugs 2018 78 761 772 10.1007/s40265-018-0908-4 29687421

286. Tanaka Y. A Review of Upadacitinib in Rheumatoid Arthritis Mod. Rheumatol. 2020 30 779 787 10.1080/14397595.2020.1782049 32530345

287. Harrington R. Al Nokhatha S.A. Conway R. JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical Data J. Inflamm. Res. 2020 13 519 10.2147/JIR.S219586 32982367 PMC7500842

288. Qureshy Z. Johnson D.E. Grandis J.R. Targeting the JAK/STAT Pathway in Solid Tumors J. Cancer Metastasis Treat. 2020 6 27 10.20517/2394-4722.2020.58 33521321 PMC7845926

289. Hosseini A. Gharibi T. Marofi F. Javadian M. Babaloo Z. Baradaran B. Janus Kinase Inhibitors: A Therapeutic Strategy for Cancer and Autoimmune Diseases J. Cell. Physiol. 2020 235 5903 5924 10.1002/jcp.29593 32072644

290. Vainchenker W. Leroy E. Gilles L. Marty C. Plo I. Constantinescu S.N. JAK Inhibitors for the Treatment of Myeloproliferative Neoplasms and Other Disorders F1000Research 2018 7 82 10.12688/f1000research.13167.1 29399328 PMC5773931

291. Kirito K. Recent Progress of JAK Inhibitors for Hematological Disorders Immunol. Med. 2023 46 131 142 10.1080/25785826.2022.2139317 36305377

292. Zhou Q. Jiang H. Zhang J. Yu W. Zhou Z. Huang P. Wang J. Xiao Z. Uridine-Cytidine Kinase 2 Promotes Metastasis of Hepatocellular Carcinoma Cells via the Stat3 Pathway Cancer Manag. Res. 2018 10 6339 6355 10.2147/CMAR.S182859 30568496 PMC6267774

293. Al-Fayoumi S. Hashiguchi T. Shirakata Y. Mascarenhas J. Singer J.W. Pilot Study of the Antifibrotic Effects of the Multikinase Inhibitor Pacritinib in a Mouse Model of Liver Fibrosis J. Exp. Pharmacol. 2018 10 9 17 10.2147/JEP.S150729 29785143 PMC5953271

294. Han Z. Liu S. Lin H. Trivett A.L. Hannifin S. Yang D. Oppenheim J.J. Inhibition of Murine Hepatoma Tumor Growth by Cryptotanshinone Involves TLR7-Dependent Activation of Macrophages and Induction of Adaptive Antitumor Immune Defenses Cancer Immunol. Immunother. 2019 68 1073 1085 10.1007/s00262-019-02338-4 31161238 PMC6584221

295. Wilson G.S. Tian A. Hebbard L. Duan W. George J. Li X. Qiao L. Tumoricidal Effects of the JAK Inhibitor Ruxolitinib (INC424) on Hepatocellular Carcinoma in Vitro Cancer Lett. 2013 341 224 230 10.1016/j.canlet.2013.08.009 23941832

296. Yang S. Luo C. Gu Q. Xu Q. Wang G. Sun H. Qian Z. Tan Y. Qin Y. Shen Y. Activating JAK1 Mutation May Predict the Sensitivity of JAK-STAT Inhibition in Hepatocellular Carcinoma Oncotarget 2016 7 5461 10.18632/oncotarget.6684 26701727 PMC4868698

297. Lee C. Cheung S.T. STAT3: An Emerging Therapeutic Target for Hepatocellular Carcinoma Cancers 2019 11 1646 10.3390/cancers11111646 31731457 PMC6895841

298. Tolomeo M. Cascio A. The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy Int. J. Mol. Sci. 2021 22 603 10.3390/ijms22020603 33435349 PMC7826746

299. Okusaka T. Morimoto M. Eguchi Y. Nakamura S. Iino S. Kageyama R. A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma Drugs R&D 2023 23 99 107 10.1007/s40268-023-00416-8 PMC10293504 37188895

300. Ren Z. Xu J. Bai Y. Xu A. Cang S. Du C. Li Q. Lu Y. Chen Y. Guo Y. Sintilimab plus a Bevacizumab Biosimilar (IBI305) versus Sorafenib in Unresectable Hepatocellular Carcinoma (ORIENT-32): A Randomised, Open-Label, Phase 2-3 Study Lancet. Oncol. 2021 22 977 990 10.1016/S1470-2045(21)00252-7 34143971

301. Yoo C. Kang J. Lim H.Y. Kim J.H. Lee M.A. Lee K.H. Kim T.Y. Ryoo B.Y. Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma Cancer Res. Treat. 2019 51 510 518 10.4143/crt.2018.226 29898591 PMC6473286

302. Tolcher A. Flaherty K. Shapiro G.I. Berlin J. Witzig T. Habermann T. Bullock A. Rock E. Elekes A. Lin C. A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers Oncologist 2018 23 658-e72 10.1634/theoncologist.2017-0325 29511132 PMC6067949

303. Bendell J.C. Hong D.S. Burris H.A. Naing A. Jones S.F. Falchook G. Bricmont P. Elekes A. Rock E.P. Kurzrock R. Phase 1, Open-Label, Dose-Escalation, and Pharmacokinetic Study of STAT3 Inhibitor OPB-31121 in Subjects with Advanced Solid Tumors Cancer Chemother. Pharmacol. 2014 74 125 130 10.1007/s00280-014-2480-2 24819685

304. Oh D.Y. Lee S.H. Han S.W. Kim M.J. Kim T.M. Kim T.Y. Heo D.S. Yuasa M. Yanagihara Y. Bang Y.J. Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors Cancer Res. Treat. 2015 47 607 615 10.4143/crt.2014.249 25715763 PMC4614199

305. Nishina T. Fujita T. Yoshizuka N. Sugibayashi K. Murayama K. Kuboki Y. Safety, Tolerability, Pharmacokinetics and Preliminary Antitumour Activity of an Antisense Oligonucleotide Targeting STAT3 (Danvatirsen) as Monotherapy and in Combination with Durvalumab in Japanese Patients with Advanced Solid Malignancies: A Phase 1 Study BMJ Open 2022 12 e055718 10.1136/BMJOPEN-2021-055718 36270753 PMC9594513

306. Roschewski M. Patel M.R. Reagan P.M. Saba N.S. Collins G.P. Arkenau H.T. de Vos S. Nuttall B. Acar M. Burke K. Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment Clin. Cancer Res. 2023 29 3301 3312 10.1158/1078-0432.CCR-22-2483 37364001 PMC10472096

307. Mohan C.D. Bharathkumar H. Bulusu K.C. Pandey V. Rangappa S. Fuchs J.E. Shanmugam M.K. Dai X. Li F. Deivasigamani A. Development of a Novel Azaspirane That Targets the Janus Kinase-Signal Transducer and Activator of Transcription (STAT) Pathway in Hepatocellular Carcinoma in Vitro and in Vivo J. Biol. Chem. 2014 289 34296 34307 10.1074/jbc.M114.601104 25320076 PMC4256360

308. Chen K.F. Tai W.T. Liu T.H. Huang H.P. Lin Y.C. Shiau C.W. Li P.K. Chen P.J. Cheng A.L. Sorafenib Overcomes TRAIL Resistance of Hepatocellular Carcinoma Cells through the Inhibition of STAT3 Clin. Cancer Res. 2010 16 5189 5199 10.1158/1078-0432.CCR-09-3389 20884624

309. Bergmann J. Müller M. Baumann N. Reichert M. Heneweer C. Bolik J. Lücke K. Gruber S. Carambia A. Boretius S. IL-6 Trans-Signaling Is Essential for the Development of Hepatocellular Carcinoma in Mice Hepatology 2017 65 89 103 10.1002/hep.28874 27770462

310. Xu J. Lin H. Wu G. Zhu M. Li M. IL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma Front. Oncol. 2021 11 760971 10.3389/fonc.2021.760971 34976809 PMC8714735

311. Kao J.T. Feng C.L. Yu C.J. Tsai S.M. Hsu P.N. Chen Y.L. Wu Y.Y. IL-6, through p-STAT3 Rather than p-STAT1, Activates Hepatocarcinogenesis and Affects Survival of Hepatocellular Carcinoma Patients: A Cohort Study BMC Gastroenterol. 2015 15 50 10.1186/s12876-015-0283-5 25908103 PMC4424593

312. Fan Y. Mao R. Yang J. NF-ΚB and STAT3 Signaling Pathways Collaboratively Link Inflammation to Cancer Protein Cell 2013 4 176 185 10.1007/s13238-013-2084-3 23483479 PMC4875500

313. Ghoshal S. Fuchs B.C. Tanabe K.K. STAT3 Is a Key Transcriptional Regulator of Cancer Stem Cell Marker CD133 in HCC Hepatobiliary Surg. Nutr. 2016 5 201 203 10.21037/hbsn.2016.03.02 27275460 PMC4876240

314. Zheng X. Xu M. Yao B. Wang C. Jia Y. Liu Q. IL-6/STAT3 Axis Initiated CAFs via up-Regulating TIMP-1 Which Was Attenuated by Acetylation of STAT3 Induced by PCAF in HCC Microenvironment Cell. Signal. 2016 28 1314 1324 10.1016/j.cellsig.2016.06.009 27297362

315. Kim B. Park B. Saffron Carotenoids Inhibit STAT3 Activation and Promote Apoptotic Progression in IL-6-Stimulated Liver Cancer Cells Oncol. Rep. 2018 39 1883 1891 10.3892/or.2018.6232 29393468

316. Yang J. Wang J. Luo J. Decreased IL-6 Induces Sensitivity of Hepatocellular Carcinoma Cells to Sorafenib Pathol. Res. Pract. 2019 215 152565 10.1016/j.prp.2019.152565 31387809

317. Pham T.H. Park H.M. Kim J. Hong J.T. Yoon D.Y. STAT3 and P53: Dual Target for Cancer Therapy Biomedicines 2020 8 637 10.3390/biomedicines8120637 33371351 PMC7767392

318. Chen R. Chen B. Siltuximab (CNTO 328): A Promising Option for Human Malignancies Drug Des. Devel. Ther. 2015 9 3455 3458 10.2147/DDDT.S86438 PMC4494175 26170629

319. Rovin B.H. van Vollenhoven R.F. Aranow C. Wagner C. Gordon R. Zhuang Y. Belkowski S. Hsu B. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Treatment with Sirukumab (CNTO 136) in Patients with Active Lupus Nephritis Arthritis Rheumatol. 2016 68 2174 2183 10.1002/art.39722 27110697 PMC5129491

320. Bayliss T.J. Smith J.T. Schuster M. Dragnev K.H. Rigas J.R. A Humanized Anti-IL-6 Antibody (ALD518) in Non-Small Cell Lung Cancer Expert Opin. Biol. Ther. 2011 11 1663 1668 10.1517/14712598.2011.627850 21995322

321. Dijkgraaf E.M. Santegoets S.J.A.M. Reyners A.K.L. Goedemans R. Wouters M.C.A. Kenter G.G. van Erkel A.R. van Poelgeest M.I.E. Nijman H.W. van der Hoeven J.J.M. A Phase I Trial Combining Carboplatin/Doxorubicin with Tocilizumab, an Anti-IL-6R Monoclonal Antibody, and Interferon-A2b in Patients with Recurrent Epithelial Ovarian Cancer Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2015 26 2141 2149 10.1093/annonc/mdv309 26216383

322. Campo S. Serlupi-Crescenzi O. Arseni B. Rossi S. Saggio I. Salone B. Cherubini G. Carminati P. De Santis R. Comparative Activity of Sant7 and Anti-IL-6, IL-6R Monoclonal Antibodies in a Murine Model of B-Cell Lymphoma Cytokine 2005 31 368 374 10.1016/j.cyto.2005.06.006 16061391

323. Oguro T. Ishibashi K. Sugino T. Hashimoto K. Tomita S. Takahashi N. Yanagida T. Haga N. Aikawa K. Suzutani T. Humanised Antihuman IL-6R Antibody with Interferon Inhibits Renal Cell Carcinoma Cell Growth in Vitro and in Vivo through Suppressed SOCS3 Expression Eur. J. Cancer 2013 49 1715 1724 10.1016/j.ejca.2012.11.038 23274199

324. Dhar D. Baglieri J. Kisseleva T. Brenner D.A. Mechanisms of Liver Fibrosis and Its Role in Liver Cancer Exp. Biol. Med. 2020 245 96 10.1177/1535370219898141 PMC7016420 31924111

325. Zhao J. Qi Y.F. Yu Y.R. STAT3: A Key Regulator in Liver Fibrosis Ann. Hepatol. 2021 21 100224 10.1016/j.aohep.2020.06.010 32702499

326. Bi Y.H. Han W.Q. Li R.F. Wang Y.J. Du Z.S. Wang X.J. Jiang Y. Signal Transducer and Activator of Transcription 3 Promotes the Warburg Effect Possibly by Inducing Pyruvate Kinase M2 Phosphorylation in Liver Precancerous Lesions World J. Gastroenterol. 2019 25 1936 10.3748/wjg.v25.i16.1936 31086462 PMC6487376

327. Park H. Lee S. Lee J. Moon H. Ro S.W. Exploring the JAK/STAT Signaling Pathway in Hepatocellular Carcinoma: Unraveling Signaling Complexity and Therapeutic Implications Int. J. Mol. Sci. 2023 24 13764 10.3390/ijms241813764 37762066 PMC10531214

328. Hin Tang J.J. Hao Thng D.K. Lim J.J. Toh T.B. JAK/STAT Signaling in Hepatocellular Carcinoma Hepatic Oncol. 2020 7 HEP18 10.2217/hep-2020-0001 PMC7137178 32273976

329. Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K Pathway in Human Disease Cell 2017 170 605 10.1016/j.cell.2017.07.029 28802037 PMC5726441

330. Glaviano A. Foo A.S.C. Lam H.Y. Yap K.C.H. Jacot W. Jones R.H. Eng H. Nair M.G. Makvandi P. Geoerger B. PI3K/AKT/MTOR Signaling Transduction Pathway and Targeted Therapies in Cancer Mol. Cancer 2023 22 138 10.1186/s12943-023-01827-6 37596643 PMC10436543

331. Terracciano L.M. Piscuoglio S. Ng C.K.Y. Hepatocellular Carcinoma: Pathology and Genetics Encycl. Cancer 2019 2019 198 210 10.1016/B978-0-12-801238-3.65261-3

332. Ligresti G. Militello L. Steelman L.S. Cavallaro A. Basile F. Nicoletti F. Stivala F. McCubrey J.A. Libra M. PIK3CA Mutations in Human Solid Tumors: Role in Sensitivity to Various Therapeutic Approaches Cell Cycle 2009 8 1352 10.4161/cc.8.9.8255 19305151 PMC3781181

333. Schulze K. Imbeaud S. Letouzé E. Alexandrov L.B. Calderaro J. Rebouissou S. Couchy G. Meiller C. Shinde J. Soysouvanh F. Exome Sequencing of Hepatocellular Carcinomas Identifies New Mutational Signatures and Potential Therapeutic Targets Nat. Genet. 2015 47 505 511 10.1038/ng.3252 25822088 PMC4587544

334. Ye L. Mayerle J. Ziesch A. Reiter F.P. Gerbes A.L. De Toni E.N. The PI3K Inhibitor Copanlisib Synergizes with Sorafenib to Induce Cell Death in Hepatocellular Carcinoma Cell Death Discov. 2019 5 86 10.1038/s41420-019-0165-7 30962952 PMC6450909

335. Zhu A.X. Abrams T.A. Miksad R. Blaszkowsky L.S. Meyerhardt J.A. Zheng H. Muzikansky A. Clark J.W. Kwak E.L. Schrag D. Phase 1/2 Study of Everolimus in Advanced Hepatocellular Carcinoma Cancer 2011 117 5094 5102 10.1002/cncr.26165 21538343 PMC3417818

336. Koeberle D. Dufour J.F. Demeter G. Li Q. Ribi K. Samaras P. Saletti P. Roth A.D. Horber D. Buehlmann M. Sorafenib with or without Everolimus in Patients with Advanced Hepatocellular Carcinoma (HCC): A Randomized Multicenter, Multinational Phase II Trial (SAKK 77/08 and SASL 29) Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2016 27 856 861 10.1093/annonc/mdw054 26884590

337. Sun E.J. Wankell M. Palamuthusingam P. McFarlane C. Hebbard L. Targeting the PI3K/Akt/MTOR Pathway in Hepatocellular Carcinoma Biomedicines 2021 9 1639 10.3390/biomedicines9111639 34829868 PMC8615614

338. Liu J. Xiao Q. Xiao J. Niu C. Li Y. Zhang X. Zhou Z. Shu G. Yin G. Wnt/β-Catenin Signalling: Function, Biological Mechanisms, and Therapeutic Opportunities Signal Transduct. Target. Ther. 2022 7 3 10.1038/s41392-021-00762-6 34980884 PMC8724284

339. Gajos-Michniewicz A. Czyz M. WNT/β-Catenin Signaling in Hepatocellular Carcinoma: The Aberrant Activation, Pathogenic Roles, and Therapeutic Opportunities Genes Dis. 2024 11 727 10.1016/j.gendis.2023.02.050 37692481 PMC10491942

340. Tian L.Y. Smit D.J. Jücker M. The Role of PI3K/AKT/MTOR Signaling in Hepatocellular Carcinoma Metabolism Int. J. Mol. Sci. 2023 24 2652 10.3390/ijms24032652 36768977 PMC9916527

341. Jang E.S. Jeong S.H. Kim J.W. Choi Y.S. Leissner P. Brechot C. Diagnostic Performance of Alpha-Fetoprotein, Protein Induced by Vitamin K Absence, Osteopontin, Dickkopf-1 and Its Combinations for Hepatocellular Carcinoma PLoS ONE 2016 11 e0151069 10.1371/journal.pone.0151069 26986465 PMC4795737

342. Suda T. Yamashita T. Sunagozaka H. Okada H. Nio K. Sakai Y. Yamashita T. Mizukoshi E. Honda M. Kaneko S. Dickkopf-1 Promotes Angiogenesis and Is a Biomarker for Hepatic Stem Cell-like Hepatocellular Carcinoma Int. J. Mol. Sci. 2022 23 2801 10.3390/ijms23052801 35269944 PMC8911428

343. Nault J.C. Mallet M. Pilati C. Calderaro J. Bioulac-Sage P. Laurent C. Laurent A. Cherqui D. Balabaud C. Rossi J.Z. High Frequency of Telomerase Reverse-Transcriptase Promoter Somatic Mutations in Hepatocellular Carcinoma and Preneoplastic Lesions Nat. Commun. 2013 4 2577 10.1038/ncomms3577 PMC3731665 23887712

344. Pinyol R. Tovar V. Llovet J.M. TERT Promoter Mutations: Gatekeeper and Driver of Hepatocellular Carcinoma J. Hepatol. 2014 61 685 687 10.1016/j.jhep.2014.05.028 24859456

345. Neiheisel A. Kaur M. Ma N. Havard P. Shenoy A.K. Wnt Pathway Modulators in Cancer Therapeutics: An Update on Completed and Ongoing Clinical Trials Int. J. Cancer 2022 150 727 740 10.1002/ijc.33811 34536299

346. Yamada K. Hori Y. Inoue S. Yamamoto Y. Iso K. Kamiyama H. Yamaguchi A. Kimura T. Uesugi M. Ito J. E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling Cancer Res. 2021 81 1052 1062 10.1158/0008-5472.CAN-20-0782 33408116

347. Voskarides K. Giannopoulou N. The Role of TP53 in Adaptation and Evolution Cells 2023 12 512 10.3390/cells12030512 36766853 PMC9914165

348. Levine A.J. P53: 800 Million Years of Evolution and 40 Years of Discovery Nat. Rev. Cancer 2020 20 471 480 10.1038/s41568-020-0262-1 32404993

349. Kruse J.P. Gu W. Modes of P53 Regulation Cell 2009 137 609 622 10.1016/j.cell.2009.04.050 19450511 PMC3737742

350. Ashcroft M. Kubbutat M.H.G. Vousden K.H. Regulation of P53 Function and Stability by Phosphorylation Mol. Cell. Biol. 1999 19 1751 1758 10.1128/MCB.19.3.1751 10022862 PMC83968

351. Barboza J.A. Iwakuma T. Terzian T. El-Naggar A.K. Lozano G. Mdm2 and Mdm4 Loss Regulates Distinct P53 Activities Mol. Cancer Res. 2008 6 947 954 10.1158/1541-7786.MCR-07-2079 18567799 PMC2699947

352. Aubrey B.J. Kelly G.L. Janic A. Herold M.J. Strasser A. How Does P53 Induce Apoptosis and How Does This Relate to P53-Mediated Tumour Suppression? Cell Death Differ. 2018 25 104 113 10.1038/cdd.2017.169 29149101 PMC5729529

353. Rivlin N. Brosh R. Oren M. Rotter V. Mutations in the P53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis Genes Cancer 2011 2 466 10.1177/1947601911408889 21779514 PMC3135636

354. Hassin O. Oren M. Drugging P53 in Cancer: One Protein, Many Targets Nat. Rev. Drug Discov. 2023 22 127 144 10.1038/s41573-022-00571-8 36216888 PMC9549847

355. Nag S. Zhang X. Srivenugopal K.S. Wang M.-H. Wang W. Zhang R. Targeting MDM2-P53 Interaction for Cancer Therapy: Are We There Yet? Curr. Med. Chem. 2014 21 553 10.2174/09298673113206660325 24180275 PMC6690199

356. Wang H. Guo M. Wei H. Chen Y. Targeting P53 Pathways: Mechanisms, Structures, and Advances in Therapy Signal Transduct. Target. Ther. 2023 8 92 10.1038/s41392-023-01347-1 36859359 PMC9977964

357. Yim S.Y. Lee J.-S. An Overview of the Genomic Characterization of Hepatocellular Carcinoma J. Hepatocell. Carcinoma 2021 8 1077 1088 10.2147/JHC.S270533 34522690 PMC8434863

358. Neuveut C. Wei Y. Buendia M.A. Mechanisms of HBV-Related Hepatocarcinogenesis J. Hepatol. 2010 52 594 604 10.1016/j.jhep.2009.10.033 20185200

359. Liu J. Ma Q. Zhang M. Wang X. Zhang D. Li W. Wang F. Wu E. Alterations of TP53 Are Associated with a Poor Outcome for Patients with Hepatocellular Carcinoma: Evidence from a Systematic Review and Meta-Analysis Eur. J. Cancer 2012 48 2328 2338 10.1016/j.ejca.2012.03.001 22459764 PMC3395767

360. Zhang W.W. Li L. Li D. Liu J. Li X. Li W. Xu X. Zhang M.J. Chandler L.A. Lin H. The First Approved Gene Therapy Product for Cancer Ad-P53 (Gendicine): 12 Years in the Clinic Hum. Gene Ther. 2018 29 160 179 10.1089/hum.2017.218 29338444

361. Xia Y. Li X. Sun W. Applications of Recombinant Adenovirus-P53 Gene Therapy for Cancers in the Clinic in China Curr. Gene Ther. 2020 20 127 141 10.2174/1566523220999200731003206 32951572

362. Guo Y. Chen Y. Zhang Y. Xu M. Guo W. Zhang J. Ma G. Liu C. Yang J. Wu X. Recombinant Human Adenovirus P53 Combined with Transcatheter Arterial Chemoembolization for Liver Cancer: A Meta-Analysis PLoS ONE 2023 18 e0295323 10.1371/journal.pone.0295323 38127912 PMC10735047

363. Yang Z.X. Wang D. Wang G. Zhang Q.H. Liu J.M. Peng P. Liu X.H. Clinical Study of Recombinant Adenovirus-P53 Combined with Fractionated Stereotactic Radiotherapy for Hepatocellular Carcinoma J. Cancer Res. Clin. Oncol. 2010 136 625 630 10.1007/s00432-009-0701-6 19882171 PMC11828154

364. Nishikawa S. Iwakuma T. Drugs Targeting P53 Mutations with FDA Approval and in Clinical Trials Cancers 2023 15 429 10.3390/cancers15020429 36672377 PMC9856662

365. Duffy M.J. Synnott N.C. O’Grady S. Crown J. Targeting P53 for the Treatment of Cancer Semin. Cancer Biol. 2022 79 58 67 10.1016/j.semcancer.2020.07.005 32741700

366. Malumbres M. Cyclin-Dependent Kinases Genome Biol. 2014 15 122 10.1186/gb4184 25180339 PMC4097832

367. Łukasik P. Załuski M. Gutowska I. Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review Int. J. Mol. Sci. 2021 22 2935 10.3390/ijms22062935 33805800 PMC7998717

368. Ding L. Cao J. Lin W. Chen H. Xiong X. Ao H. Yu M. Lin J. Cui Q. The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer Int. J. Mol. Sci. 2020 21 1960 10.3390/ijms21061960 32183020 PMC7139603

369. Ghafouri-Fard S. Khoshbakht T. Hussen B.M. Dong P. Gassler N. Taheri M. Baniahmad A. Dilmaghani N.A. A Review on the Role of Cyclin Dependent Kinases in Cancers Cancer Cell Int. 2022 22 325 10.1186/s12935-022-02747-z 36266723 PMC9583502

370. Zhang M. Zhang L. Hei R. Li X. Cai H. Wu X. Zheng Q. Cai C. CDK Inhibitors in Cancer Therapy, an Overview of Recent Development Am. J. Cancer Res. 2021 11 1913 34094661 PMC8167670

371. Syn N.L. Lim P.L. Kong L.R. Wang L. Wong A.L.A. Lim C.M. Loh T.K.S. Siemeister G. Goh B.C. Hsieh W.S. Pan-CDK Inhibition Augments Cisplatin Lethality in Nasopharyngeal Carcinoma Cell Lines and Xenograft Models Signal Transduct. Target. Ther. 2018 3 9 10.1038/s41392-018-0010-0 29666673 PMC5897350

372. Jessen B.A. Lee L. Koudriakova T. Haines M. Lundgren K. Price S. Nonomiya J. Lewis C. Stevens G.J. Peripheral White Blood Cell Toxicity Induced by Broad Spectrum Cyclin-Dependent Kinase Inhibitors J. Appl. Toxicol. 2007 27 133 142 10.1002/jat.1177 17211896

373. Massard C. Soria J.C. Anthoney D.A. Proctor A. Scaburri A. Pacciarini M.A. Laffranchi B. Pellizzoni C. Kroemer G. Armand J.P. A First in Man, Phase I Dose-Escalation Study of PHA-793887, an Inhibitor of Multiple Cyclin-Dependent Kinases (CDK2, 1 and 4) Reveals Unexpected Hepatotoxicity in Patients with Solid Tumors Cell Cycle 2011 10 963 970 10.4161/cc.10.6.15075 21368575

374. DiPippo A.J. Patel N.K. Barnett C.M. Cyclin-Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future Pharmacotherapy 2016 36 652 667 10.1002/phar.1756 27087139

375. Kwapisz D. Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Palbociclib, Ribociclib, and Abemaciclib Breast Cancer Res. Treat. 2017 166 41 54 10.1007/s10549-017-4385-3 28741274

376. Beaver J.A. Amiri-Kordestani L. Charlab R. Chen W. Palmby T. Tilley A. Zirkelbach J.F. Yu J. Liu Q. Zhao L. FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer Clin. Cancer Res. 2015 21 4760 4766 10.1158/1078-0432.CCR-15-1185 26324739

377. Shah A. Bloomquist E. Tang S. Fu W. Bi Y. Liu Q. Yu J. Zhao P. Palmby T.R. Goldberg K.B. FDA Approval: Ribociclib for the Treatment of Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer Clin. Cancer Res. 2018 24 2999 3004 10.1158/1078-0432.CCR-17-2369 29437768

378. Royce M. Osgood C. Mulkey F. Bloomquist E. Pierce W.F. Roy A. Kalavar S. Ghosh S. Philip R. Rizvi F. FDA Approval Summary: Abemaciclib with Endocrine Therapy for High-Risk Early Breast Cancer J. Clin. Oncol. 2022 40 1155 1162 10.1200/JCO.21.02742 35084948 PMC8987222

379. Digiacomo G. Fumarola C. La Monica S. Bonelli M.A. Cretella D. Alfieri R. Cavazzoni A. Galetti M. Bertolini P. Missale G. Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib with Regorafenib Induces Enhanced Anti-Tumor Effects in Hepatocarcinoma Cell Lines Front. Oncol. 2020 10 563249 10.3389/fonc.2020.563249 33072590 PMC7539564

380. Limousin W. Laurent-Puig P. Ziol M. Ganne-Carrié N. Nahon P. Ait-Omar A. Seror O. Sidali S. Campani C. Blanc P. Molecular-Based Targeted Therapies in Patients with Hepatocellular Carcinoma and Hepato-Cholangiocarcinoma Refractory to Atezolizumab/Bevacizumab J. Hepatol. 2023 79 1450 1458 10.1016/j.jhep.2023.08.017 37647991

381. Wang H. Liao P. Zeng S.X. Lu H. Co-Targeting P53-R249S and CDK4 Synergistically Suppresses Survival of Hepatocellular Carcinoma Cells Cancer Biol. Ther. 2020 21 269 277 10.1080/15384047.2019.1685289 31747859 PMC7012101

382. Jindal A. Thadi A. Shailubhai K. Hepatocellular Carcinoma: Etiology and Current and Future Drugs J. Clin. Exp. Hepatol. 2019 9 221 232 10.1016/j.jceh.2019.01.004 31024205 PMC6477125

383. Digiacomo G. Fumarola C. La Monica S. Bonelli M. Cavazzoni A. Galetti M. Terenziani R. Eltayeb K. Volta F. Zoppi S. CDK4/6 Inhibitors Improve the Anti-Tumor Efficacy of Lenvatinib in Hepatocarcinoma Cells Front. Oncol. 2022 12 942341 10.3389/fonc.2022.942341 35936714 PMC9354684

384. Robertson I.B. Rifkin D.B. Unchaining the Beast; Insights from Structural and Evolutionary Studies on TGFβ Secretion, Sequestration, and Activation Cytokine Growth Factor Rev. 2013 24 355 372 10.1016/j.cytogfr.2013.06.003 23849989 PMC3780968

385. Budi E.H. Duan D. Derynck R. Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility Trends Cell Biol. 2017 27 658 672 10.1016/j.tcb.2017.04.005 28552280

386. Derynck R. Budi E.H. Specificity, Versatility, and Control of TGF-β Family Signaling Sci. Signal. 2019 12 eaav5183 10.1126/scisignal.aav5183 30808818 PMC6800142

387. Liu S. Ren J. Ten Dijke P. Targeting TGFβ Signal Transduction for Cancer Therapy Signal Transduct. Target. Ther. 2021 6 8 10.1038/s41392-020-00436-9 33414388 PMC7791126

388. Oberhammer F.A. Pavelka M. Sharma S. Tiefenbacher R. Purchio A.F. Bursch W. Schulte-Hermann R. Induction of Apoptosis in Cultured Hepatocytes and in Regressing Liver by Transforming Growth Factor Beta 1 Proc. Natl. Acad. Sci. USA 1992 89 5408 5412 10.1073/pnas.89.12.5408 1608949 PMC49301

389. Sánchez A. Álvarez A.M. Benito M. Fabregat I. Apoptosis Induced by Transforming Growth Factor-Beta in Fetal Hepatocyte Primary Cultures: Involvement of Reactive Oxygen Intermediates J. Biol. Chem. 1996 271 7416 7422 10.1074/jbc.271.13.7416 8631767

390. Polyak K. Kato J.Y. Solomon M.J. Sherr C.J. Massague J. Roberts J.M. Koff A. P27Kip1, a Cyclin-Cdk Inhibitor, Links Transforming Growth Factor-Beta and Contact Inhibition to Cell Cycle Arrest Genes Dev. 1994 8 9 22 10.1101/gad.8.1.9 8288131

391. Giannelli G. Bergamini C. Fransvea E. Sgarra C. Antonaci S. Laminin-5 with Transforming Growth Factor-Beta1 Induces Epithelial to Mesenchymal Transition in Hepatocellular Carcinoma Gastroenterology 2005 129 1375 1383 10.1053/j.gastro.2005.09.055 16285938

392. Malfettone A. Soukupova J. Bertran E. Crosas-Molist E. Lastra R. Fernando J. Koudelkova P. Rani B. Fabra Á. Serrano T. Transforming Growth Factor-β-Induced Plasticity Causes a Migratory Stemness Phenotype in Hepatocellular Carcinoma Cancer Lett. 2017 392 39 50 10.1016/j.canlet.2017.01.037 28161507

393. Gotzmann J. Fischer A.N.M. Zojer M. Mikula M. Proell V. Huber H. Jechlinger M. Waerner T. Weith A. Beug H. A Crucial Function of PDGF in TGF-Beta-Mediated Cancer Progression of Hepatocytes Oncogene 2006 25 3170 3185 10.1038/sj.onc.1209083 16607286

394. Soukupova J. Malfettone A. Hyroššová P. Hernández-Alvarez M.I. Peñuelas-Haro I. Bertran E. Junza A. Capellades J. Giannelli G. Yanes O. Role of the Transforming Growth Factor-β in Regulating Hepatocellular Carcinoma Oxidative Metabolism Sci. Rep. 2017 7 12486 10.1038/s41598-017-12837-y 28970582 PMC5624948

395. Kim J. Hong S.J. Lim E.K. Yu Y.S. Kim S.W. Roh J.H. Do I.G. Joh J.W. Kim D.S. Expression of Nicotinamide N-Methyltransferase in Hepatocellular Carcinoma Is Associated with Poor Prognosis J. Exp. Clin. Cancer Res. 2009 28 20 10.1186/1756-9966-28-20 19216803 PMC2657806

396. Campagna R. Vignini A. NAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health Antioxidants 2023 12 376 10.3390/antiox12020376 36829935 PMC9952603

397. Li J. You S. Zhang S. Hu Q. Wang F. Chi X. Zhao W. Xie C. Zhang C. Yu Y. Elevated N-Methyltransferase Expression Induced by Hepatic Stellate Cells Contributes to the Metastasis of Hepatocellular Carcinoma via Regulation of the CD44v3 Isoform Mol. Oncol. 2019 13 1993 2009 10.1002/1878-0261.12544 31294922 PMC6717763

398. Caballero-Díaz D. Bertran E. Peñuelas-Haro I. Moreno-Càceres J. Malfettone A. López-Luque J. Addante A. Herrera B. Sánchez A. Alay A. Clathrin Switches Transforming Growth Factor-β Role to pro-Tumorigenic in Liver Cancer J. Hepatol. 2020 72 125 134 10.1016/j.jhep.2019.09.012 31562907

399. Feng T. Dzieran J. Gu X. Marhenke S. Vogel A. Machida K. Weiss T.S. Ruemmele P. Kollmar O. Hoffmann P. Smad7 Regulates Compensatory Hepatocyte Proliferation in Damaged Mouse Liver and Positively Relates to Better Clinical Outcome in Human Hepatocellular Carcinoma Clin. Sci. 2015 128 761 774 10.1042/CS20140606 PMC10618913 25602745

400. Badawi M. Kim J. Dauki A. Sutaria D. Motiwala T. Reyes R. Wani N. Kolli S. Jiang J. Coss C.C. CD44 Positive and Sorafenib Insensitive Hepatocellular Carcinomas Respond to the ATP-Competitive MTOR Inhibitor INK128 Oncotarget 2018 9 26032 26045 10.18632/oncotarget.25430 29899840 PMC5995255

401. Dzieran J. Fabian J. Feng T. Coulouarn C. Ilkavets I. Kyselova A. Breuhahn K. Dooley S. Meindl-Beinker N.M. Comparative Analysis of TGF-β/Smad Signaling Dependent Cytostasis in Human Hepatocellular Carcinoma Cell Lines PLoS ONE 2013 8 e72252 10.1371/journal.pone.0072252 23991075 PMC3750029

402. Lee H.-J. Recent Advances in the Development of TGF-β Signaling Inhibitors for Anticancer Therapy J. Cancer Prev. 2020 25 213 222 10.15430/JCP.2020.25.4.213 33409254 PMC7783242

403. Huang C.Y. Chung C.L. Hu T.H. Chen J.J. Liu P.F. Chen C.L. Recent Progress in TGF-β Inhibitors for Cancer Therapy Biomed. Pharmacother. 2021 134 111046 10.1016/j.biopha.2020.111046 33341049

404. Zhu A.X. Kang Y.K. Yen C.J. Finn R.S. Galle P.R. Llovet J.M. Assenat E. Brandi G. Pracht M. Lim H.Y. Ramucirumab after Sorafenib in Patients with Advanced Hepatocellular Carcinoma and Increased α-Fetoprotein Concentrations (REACH-2): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial Lancet. Oncol. 2019 20 282 296 10.1016/S1470-2045(18)30937-9 30665869