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Decoding the mechanisms underlying breast cancer brain metastasis: paving the way for precision therapeutics.

The development of brain metastasis is a major cause of significantly reduced survival in breast cancer patients. The initiation and progression of breast cancer brain metastasis (BCBM) involve multiple distinct molecular pathways and reprogramming of the tumor microenvironment (TME). This review systematically summarizes key mechanisms underlying BCBM, including epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and the spatiotemporal dynamics of metabolic reprogramming regulated by critical signaling pathways during brain colonization. In particular, we highlight

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… Signaling pathways such as TGF-β, Wnt/β-catenin, and Hippo regulate ECM-modifying enzymes, such as MMPs, heparanases and LOX, as well as ECM proteins, thereby altering the mechanical and structural properties of the microenvironment and facilitating BBB disruption and tumor cell colonization in the brain …

Exosomes: A new option for osteoporosis treatment.

Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These ca

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… Heparanase involvement in exosome formation. Adv Exp Med Biol . 2020 ; 1221 : 285 – 307 . 32274714 10.1007/978-3-030-34521-1_10 [13] Jadli AS Ballasy N Edalat P . Inside(sight) of tiny communicator: exosome biogenesis, secretion, and uptake. … Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Res . 2015 ; 25 : 412 – 28 . 25732677 10.1038/cr.2015.29 PMC4387558 [32] Gangalum RK Bhat AM Kohan SA . …

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy.

Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) ne

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… Moreover, the authors hypothesized that increased TNF-α levels caused the upregulation of heparanase (HSPE) expression, an endoglycosidase involved in the production of inflammatory cytokines, which was secondary to the development of the neuropathy ( 204 ). …

Multiple Liver Nodules Mimicking Metastatic Disease as Initial Presentation of Multiple Myeloma.

Multiple myeloma is a malignant clonal proliferation of plasma cells in the bone marrow preceded by monoclonal gammopathy of undetermined significance. Initial presentation of multiple myeloma as extramedullary spread in soft tissues particularly in the liver is uncommon. We report a case of a 74-year-old African American female who presented with epigastric pain, hematemesis, elevated alkaline phosphatase, and gamma-glutamyl transferase. Initial impression was peptic ulcer disease; however, ultrasound and CT scan of the abdomen showed multiple liver nodules and perihepatic lymphadenopathy sug

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… The pattern of plasma cell infiltration was described as either diffuse sinusoidal, nodular, portal, or mixed [ 7 – 11 ], while the mechanisms of extramedullary spread included decreased expression of adhesion molecules, downregulation of chemokine receptors, downregulation of tetraspanins, increased heparanase …

Pathophysiology and therapeutic advances in myeloma bone disease.

Bone disease is the most common complication in patients with multiple myeloma (MM), and it may lead to skeletal-related events (SREs) such as bone pain, pathological fractures, and spinal cord compression, which impair a patients' quality of life and survival. The pathogenesis of myeloma bone disease (MBD) involves disruption of bone reconstitution balance including excessive activation of osteoclasts, inhibition of osteoblasts, and participation of osteocytes and bone marrow stromal cells. Various factors, such as the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OP

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… Heparanase‐enhanced shedding of Syndecan‐1 and its role in driving disease pathogenesis and progression. J Histochem Cytochem. 2020;68:823‐840. 10.1369/0022155420937087 20. Sugatani T, Alvarez UM, Hruska KA. …

Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors.

Chimeric antigen receptor (CAR) T cells in solid tumors have so far yielded limited results, in terms of therapeutic effects, as compared to the dramatic results observed for hematological malignancies. Many factors involve both the tumor cells and the microenvironment. The lack of specific target antigens and severe, potentially fatal, toxicities caused by on-target off-tumor toxicities constitute major hurdles. Furthermore, the tumor microenvironment is usually characterized by chronic inflammation, the presence of immunosuppressive molecules, and immune cells that can reduce CAR T cell effi

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… For instance, CAR T cells engineered to express heparanase, which degrades the heparan sulfate component of the ECM, have shown better infiltration and tumor clearance both in vitro and in animal models [ 11 ]. … Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes Nat. Med. 2015 21 524 529 10.1038/nm.3833 25849134 PMC4425589 12. Newport E.L. Pedrosa A.R. Njegic A. Hodivala-Dilke K.M. Munoz-Felix J.M. …

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination.

The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) rem

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… Consistently, heparanase, by enhancing MMP-9 expression, induces expression and shedding of Sdc-1 in myeloma and BC. … Therefore, targeting Sdc-1 and/or inhibiting MMP-9 or heparanase could represent yet another potential therapeutic strategy for BC [ 285 ]. 6. …

Targetable pathways for drug repurposing in gastric cancer.

Gastric cancer (GC) is both the fifth most common cancer worldwide and the fifth in mortality. Owing to a lack of symptoms in the early stages and unspecific clinical presentation in the later stages, GC is usually diagnosed at advanced stages. This means that only approximately 60% of patients are eligible for curative treatment, and overall, GC patients have a 5-year survival rate of only 28.3%, underscoring the importance of developing new treatment strategies. Drug repurposing involves identifying new therapeutic uses for approved drugs and is a promising strategy for cancer treatment beca

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… The proposed mechanism of action was the inhibition of heparanase as a result of the downregulation of NF-κB signaling. Heparanase plays an important role in the metastatic process of GC[ 98 ]. …

New Progress in Improving the Delivery Methods of Bisphosphonates in the Treatment of Bone Tumors.

Bone tumors are tumors that occur in the bone or its accessory tissues, including primary tumors and metastatic tumors. The main mechanism of bisphosphonate is to inhibit the resorption of destructive bone, inhibit the activity of osteoclasts and reduce the concentration of blood calcium. Therefore, bisphosphonates can be used for malignant hypercalcaemia, pain caused by osteolytic bone metastasis, prevention of osteolytic bone metastasis, multiple myeloma osteopathy, improving radiosensitivity and so on. However, the traditional administration of bisphosphonates can cause a series of adverse

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… The mechanism may be that heparanase secreted by tumor cells can degrade LMWH and eliminate the shielding of lipids in vitro. In addition, the interaction between heparanase and LMWH also increased the retention time of liposomes. …

The Potential Role of Proinflammatory Cytokines and Complement Components in the Development of Drug-Induced Neuropathy in Patients with Multiple Myeloma.

The launch of novel chemotherapeutic agents-in particular, proteasome inhibitors and immunomodulatory drugs-dramatically changed multiple myeloma (MM) therapy, improving the response rate and prolonging progression-free survival. However, none of the anti-MM drugs are deprived of side effects. Peripheral neuropathy (PN) seems to be one of the most pressing problems. Despite extensive research in this area, the pathogenesis of drug-induced peripheral neuropathy (DiPN) has not yet been fully elucidated. In the present study, we aimed to assess the potential relationship between proinflammatory f

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… Peripheral neuropathy following bortezomib therapy in multiple myeloma patients: Association with cumulative dose, heparanase, and TNF-α Ann. Hematol. 2019 98 2793 2803 10.1007/s00277-019-03816-6 31650289 18. Alé A. Bruna J. Morell M. Velde H. Monbaliu J. Navarro X. Udina E. …

Acute Kidney Injury in Oncology Patients.

With rapid progress in cancer diagnosis and treatment in the last two decades, outcomes in oncological patients have improved significantly. However, the incidence of acute kidney injury (AKI) in this population has also increased significantly. AKI complicates many aspects of patients' care and adversely affects their prognoses; thus, accurately diagnosing the risk factors for AKI ensures appropriate management. AKI may be caused by pre-renal, intrinsic renal, and post-renal reasons, as well as for combined reasons. This review summarizes the potential etiologies of AKI according to the three

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… A possible explanation for the association between FSGS and hematological tumors is that vascular endothelial growth factor and heparanase have been reported to alter glomerular permeability in patients with FSGS 25 . …

Defibrotide for Protecting Against and Managing Endothelial Injury in Hematologic Malignancies and COVID-19.

Defibrotide, which is approved for treating hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), exhibits pleiotropic anti-inflammatory, anti-thrombotic, and fibrinolytic properties, conferring broad endothelial protective effects. Given these mechanisms, defibrotide has potential utility in various conditions involving endothelial injury or activation. In this review we outline the endothelial-protective mechanisms of defibrotide and comprehensively summarize current evidence supporting its applications in hematologic malignancies, including the prevention and treatment

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… It provides endothelial protection through the maintenance of sinusoidal vascular integrity and the reduction in heparanase expression [ 45 , 46 ], and exerts anti-inflammatory effects via reductions in TNFα, VCAM-1, and p38 mitogen-activated protein kinase (MAPK) as well as Akt phosphorylation [ 45 … DF may also inhibit expression and activity of heparanase, modulate endothelial cell injury by downregulating expression of endothelial cell adhesion molecules such as E-selectin, VCAM-1, and ICAM-1, and increase endothelial cell release of anti-inflammatory cytokines. …

Engineering enhanced CAR T-cells for improved cancer therapy.

Chimeric antigen receptor (CAR) T-cell therapies have evolved from a research tool to a paradigm-shifting therapy with impressive responses in B cell malignancies. This review summarizes the current state of the CAR T-cell field, focusing on CD19- and B cell maturation antigen-directed CAR T-cells, the most developed of the CAR T-cell therapies. We discuss the many challenges to CAR-T therapeutic success and innovations in CAR design and T-cell engineering aimed at extending this therapeutic platform beyond hematologic malignancies.

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… CAR T-cells naturally express low levels of enzymes that degrade ECM components, but engineering the expression of heparanase was shown to improve their capacity to degrade ECM proteoglycans, thereby promoting CAR T-cell entry into stroma-rich tumors and antitumor activity 178 . … Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 21, 524–529, doi: 10.1038/nm.3833 (2015). 179. Feig C et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. …

Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases.

Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution str

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… A phase I clinical trial of such a latter compound (Roneparstat, SST0001), which has competitive heparanase inhibitor properties, has been conducted in patients suffering from multiple myeloma, regarding its anti-myeloma effect, dosing, and safety profile ( https://clinicaltrials.gov/ct2/show/record/ … Phase I study of the heparanase inhibitor Roneparstat: An innovative approach for multiple myeloma therapy. Haematologica. 2018 doi: 10.3324/haematol.2017.182865. 172. Peterson P., Whatcott C., Siddiqui-Jain A., Weitman S., Kieran M., Bearss D.J., Warner S.L. …

Skeletal metastasis: treatments, mouse models, and the Wnt signaling.

Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process o

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… Additionally, endocrine factors such as heparanase, osteopontin, and matrix metalloproteases are produced by primary tumors and go into circulation before actual metastasis occurs, setting up a “pre-metastatic niche” [16] – [19] . … The role of endothelial cell adhesion molecules Cancer Metastasis Rev 1990 9 175 189 2292135 10.1007/BF00046359 16 Kelly T Suva LJ Huang Y Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases Cancer Res 2005 65 5778 5784 15994953 10.1158 …

Knockdown of LINC00963 targets miR-1252-5p to reduce inflammatory levels and ECM degradation in nucleus pulposus cells of IDD.

BACKGROUND: In middle-aged and older adults, intervertebral disc degeneration (IDD) is a major cause of chronic low back pain and disability. This pathological process is closely linked to the activation of inflammatory factors resulting from an imbalance in extracellular matrix (ECM) metabolism and abnormalities in Nucleus pulposus cells (NPCs). This study aims to clarify the functional importance of LINC00963 in IDD and its potential molecular mechanisms. METHODS: 102 IDD patients and 88 scoliosis controls were enrolled. IL-1β-stimulated NPCs modeled IDD in vitro. RT-qPCR detected LINC00963,

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… MicroRNA-1252-5p Associated with Extracellular Vesicles Enhances Bortezomib Sensitivity in Multiple Myeloma Cells by Targeting Heparanase. OncoTargets therapy. 2021;14:455–67. 50. Che Z, Xueqin J, Zhang Z. LncRNA OIP5-AS1 accelerates intervertebral disc degeneration by targeting miR-25-3p. …

A prognostic model for patients with primary extramedullary multiple myeloma.

Background: Extramedullary disease is a manifestation of multiple myeloma, the prognosis of which remains poor even in the era of novel drugs. Therefore, we aimed to develop a predictive model for patients with primary extramedullary multiple myeloma (EMM). Methods: Clinical and laboratory data of patients diagnosed with primary EMM between July 2007 and July 2021 were collected and analyzed. Univariate and least absolute shrinkage and selection operation Cox regression analyses (LASSO) were used to select prognostic factors for overall survival (OS) to establish a nomogram prognostic model. T

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… The possible mechanism of MM extramedullary spread may include decreased expression of adhesion molecules, downregulation of chemokine receptors and tetraspanins expression, increased heparanase-1 expression ( Bladé et al., 2011 ). …

Bone Metastasis of Breast Cancer: Molecular Mechanisms and Therapeutic Strategies.

Bone metastasis is a common complication of many types of advanced cancer, including breast cancer. Bone metastasis may cause severe pain, fractures, and hypercalcemia, rendering clinical management challenging and substantially reducing the quality of life and overall survival (OS) time of breast cancer patients. Studies have revealed that bone metastasis is related to interactions between tumor cells and the bone microenvironment, and involves complex molecular biological mechanisms, including colonization, osteolytic destruction, and an immunosuppressive bone microenvironment. Agents inhibi

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… Primary tumor cells modulate bone marrow, to facilitate tumor cell localization and colonization, by producing circulating factors that regulate cells in the bone microenvironment; for example, heparanase and PTHrP expressed by breast cancer cells promote bone resorption in the absence of detectable … Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases Cancer Res. 2005 65 5778 5784 10.1158/0008-5472.CAN-05-0749 15994953 88. Roodman G. Biology of osteoclast activation in cancer J. Clin. …

The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated tha

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… Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity. J. Biol. Chem. 2011;286:6490–6499. doi: 10.1074/jbc.M110.183277. 54. Kido S., Kuriwaka-Kido R., Imamura T., Ito Y., Inoue D., Matsumoto T. …

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