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Breast cancer metastasis to the bone: mechanisms of bone loss.

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts

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… PMC3047387 McHayleh W Ellerman J Roodman D Rosen CL Hematologic malignancies and bone Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 2008 7 Washington, DC: American Society for Bone and Mineral Research 379 382 full_text Yang Y Ren Y Ramani VC Nan L Suva LJ Sanderson RD Heparanase …

Tumor microenvironment signaling and therapeutics in cancer progression.

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss t

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… ‐2 ‐ targets EDB | Advanced renal cell carcinoma, metastatic melanoma | NCT01058538 (I) NCT01055522 (II) | [ 49 , 50 ] RO5429083 | CD44 antibody ‐ inhibits the mRNA transcription of CD44 or CD44v | Neoplasms, Myelogenous Leukemia, acute | NCT01358903NCT01641250 | [ 51 , 52 ] Ronespartat (SST0001) | Heparanase …

NK cell based immunotherapy against oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC), a major subtype of head and neck cancers, presents significant challenges due to its aggressive feature and limited therapeutic efficacy of conventional treatments. In response to these challenges, Natural Killer (NK) cells, a vital component of the innate immune system, are being explored for their therapeutic potential in OSCC due to their inherent ability to target and eliminate cancer cells without prior sensitization. This review uniquely focuses on the evolving role of NK cells specifically in OSCC, incorporating recent advancements in CAR-NK cell eng

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… Wang C et al. studied how heparanase (HPSE) promotes malignant characteristics in human oral squamous carcinoma cells by regulating EMT-related molecules and levels of infiltrating NK cells ( 174 ). …

CAR-T Cell Therapy: Managing Side Effects and Overcoming Challenges.

Chimeric antigen receptor T (CAR-T) cell therapy is an innovative and promising approach to treat cancer. Clinical trials have demonstrated remarkable results, providing hope for patients who have exhausted more traditional therapies. However, this new therapy is not without challenges, as significant side effects have been associated with it. Cytokine release syndrome (CRS) is a widely recognized and consequential side effect of CAR-T cell therapy. Neurological toxicity is another potential side effect that can cause confusion and seizures in some patients. Hematologic toxicities, such as ane

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… Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 2015;21:524–9. doi: 10.1038/nm.3833. 10. Titov A, Petukhov A, Staliarova A, Motorin D, Bulatov E, Shuvalov O, et al. …

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23.

Multiple Myeloma (MM) induces bone destruction, decreases bone formation, and increases marrow angiogenesis in patients. We reported that osteocytes (Ocys) directly interact with MM cells to increase tumor growth and expression of Ocy-derived factors that promote bone resorption and suppress bone formation. However, the contribution of Ocys to enhanced marrow vascularization in MM is unclear. Since the MM microenvironment is hypoxic, we assessed if hypoxia and/or interactions with MM cells increases pro-angiogenic signaling in Ocys. Hypoxia and/or co-culture with MM cells significantly increas

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… Suvannasankha A FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells Oncotarget 2015 6 19647 19660 10.18632/oncotarget.3794 25944690 PMC4637311 18. …

Cardiovascular disease and chimeric antigen receptor cellular therapy.

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary personalized therapy that has significantly impacted the treatment of patients with hematologic malignancies refractory to other therapies. Cytokine release syndrome (CRS) is a major side effect of CAR T therapy that can occur in 70-90% of patients, with roughly 40% of patients at grade 2 or higher. CRS can cause an intense inflammatory state leading to cardiovascular complications, including troponin elevation, arrhythmias, hemodynamic instability, and depressed left ventricular systolic function. There are currently no stand

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… Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes . Nat Med. ( 2015 ) 21 : 524 – 9 . 10.1038/nm.3833 25849134 PMC4425589 16. Wang LC Lo A Scholler J Sun J Majumdar RS Kapoor V . …

Guided immunotherapy for residual solid tumor: integrating platelets and CAR T cells to reduce post-surgical recurrence.

Postoperative recurrence remains a major obstacle to durable remission in patients with solid tumors, even after complete macroscopic resection. Growing evidence suggests that surgery creates a transient yet highly permissive biological window characterized by inflammatory signaling, coagulation activation, endothelial disruption, and systemic immune suppression. Together, these processes foster a protective niche that enables microscopic residual disease to evade immune surveillance and initiate metastatic outgrowth. Although modern adjuvant therapies have improved outcomes, their effectivene

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… Heparanase ECM-degrading enzyme Cleavage of heparan sulfate-rich matrices → release of growth factors, invasion, angiogenesis Heparan sulfate proteoglycans, VEGF/FGF axis Pro-tumor [ 121 , 122 ] Table 2 Major extracellular matrix components and remodeling programs in solid tumors: structural alterations … Heparanase | ECM-degrading enzyme | Cleavage of heparan sulfate-rich matrices → release of growth factors, invasion, angiogenesis | Heparan sulfate proteoglycans, VEGF/FGF axis | Pro-tumor | [ 121 , 122 ] Metabolic reprogramming in the tumor microenvironment and emerging therapeutic strategies Metabolic …

Животные модели периферической нейропатии, вызванной химиотерапией, для гематологических заболеваний: обзор.

Химиотерапия это one основные виды лечения гематологовых магнестов. Однако периферическая нейропатия, вызванная химиотерапией (CIPN) one Наиболее часто встречающиеся долгосрочные токсичные реакции в химиотерапии, а также случаи CIPN влияют на качество жизни пациентов и могут приводить к прерыванию химиотерапии в тяжелых случаях, снижая тем самым эффективность химиотерапии. В настоящее время мы резюмируем существующие зверские модели CIPN, включая характеристики нескольких общих животных моделей, таких, как периферическая нейропатия, вызванная бортезомибами, периферическая нейропатия, вызванная

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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(12):2793‐2803. 10.1007/s00277-019-03816-6 17. Bruna J, Udina E, Alé A, et al. …

Targeting CD44 and other pleiotropic co-receptors as a means for broad inhibition of tumor growth and metastasis.

Although progress has been made in the treatment of cancer, particularly for the four major types of cancers affecting the lungs, colon, breast and prostate, resistance to cancer treatment often emerges upon inhibition of major signaling pathways, which leads to the activation of additional pathways as a last-resort survival mechanism by the cancer cells. This signaling plasticity provides cancer cells with a level of operational freedom, reducing treatment efficacy. Plasticity is a characteristic of cancer cells that are not only able to switch signaling pathways but also from one cellular st

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… Katakam SK, Pelucchi P, Cocola C, Reinbold R, Vlodavsky I, Greve B, Gotte M (2020) Syndecan-1-Dependent regulation of Heparanase affects invasiveness, Stem Cell properties, and therapeutic resistance of Caco2 Colon cancer cells. Front Oncol 10:774 52. …

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy.

Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we

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… Heparanase Stimulation of Protease Expression Implicates It as a Master Regulator of the Aggressive Tumor Phenotype in Myeloma. J. Biol. Chem. 2008;283:32628–32636. doi: 10.1074/jbc.M806266200. 26. …

Understanding the Mechanisms of Resistance to CAR T-Cell Therapy in Malignancies.

Taking advantage of the immune system to exert an antitumor effect is currently a novel approach in cancer therapy. Adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) targeting a desired antigen has shown extraordinary antitumor activity, especially in refractory and relapsed B-cell malignancies. The most representative in this respect, as well as the most successful example, is CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL). However, with the widespread use of CAR T-cell therapy, problems of resistance and relapse are starting to be co

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… CAR T cells can also be engineered to secrete some enzymes or chemokines, such as heparanase, to promote the infiltration of immune effector cells into tumor, especially in solid tumors. For antibodies against murine CAR scFv, the application of humanized CAR T cells is the best solution. …

Targeting dorsal root ganglia for chemotherapy-induced peripheral neuropathy: from bench to bedside.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design

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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. 132. Broyl A, Corthals SL, Jongen JL, et al. …

Extracellular Vesicles in Tumors: A Potential Mediator of Bone Metastasis.

As one of the most common metastatic sites, bone has a unique microenvironment for the growth and prosperity of metastatic tumor cells. Bone metastasis is a common complication for tumor patients and accounts for 15-20% of systemic metastasis, which is only secondary to lung and liver metastasis. Cancers prone to bone metastasis include lung, breast, and prostate cancer. Extracellular vesicles (EVs) are lipid membrane vesicles released from different cell types. It is clear that EVs are associated with multiple biological phenomena and are crucial for intracellular communication by transportin

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… Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bone metastases. Cancer Res. 65 5778–5784. 10.1158/0008-5472.CAN-05-0749 Kianercy A., Pienta K. J. (2016). …

Megakaryocyte Contribution to Bone Marrow Fibrosis: many Arrows in the Quiver.

In Primary Myelofibrosis (PMF), megakaryocyte dysplasia/hyperplasia determines the release of inflammatory cytokines that, in turn, stimulate stromal cells and induce bone marrow fibrosis. The pathogenic mechanism and the cells responsible for progression to bone marrow fibrosis in PMF are not completely understood. This review article aims to provide an overview of the crucial role of megakaryocytes in myelofibrosis by discussing the role and the altered secretion of megakaryocyte-derived soluble factors, enzymes and extracellular matrices that are known to induce bone marrow fibrosis.

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… factors, for example, antithrombin, protein S, C1-inhibitor, TFPI and protease nexin 2 and pro-fibrinolytic proteins such as plasminogen and plasmin have been all localized in α-granules. 25 Differently from α-granules, secretory lysosomes contain distinct acid hydrolases, such as beta-hexosaminidase, heparanase …

Targeted Therapies in Adult B-Cell Malignancies.

B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is c

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… Syndecan-1 is cleaved by heparanase, an endo- β -o-glucuronidase, secreted by osteoclasts [ 36 ]. …

Revolutionizing the treatment for nasopharyngeal cancer: the impact, challenges and strategies of stem cell and genetically engineered cell therapies.

Nasopharyngeal carcinoma (NPC) is a distinct malignancy of the nasopharynx and is consistently associated with the Epstein-Barr virus (EBV) infection. Its unique anatomical location and complex aetiology often result in advanced-stage disease at first diagnosis. While radiotherapy (RT) and chemotherapy have been the mainstays of treatment, they often fail to prevent tumour recurrence and metastasis, leading to high rates of treatment failure and mortality. Recent advancement in cell-based therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown great promise in hematologic

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… For instance, CAR-T cells expressing heparanase (HPSE) can break down ECM components and reduce fibrosis, improving immune cell infiltration and antitumour effects ( 183 ). …

Genome-edited allogeneic CAR-T cells: the next generation of cancer immunotherapies.

Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized cancer immunotherapy, particularly in hematological malignancies. However, the clinical application of autologous CAR-T cells faces significant high cost and manufacturing challenges. Universal allogeneic CAR-T cells, derived from healthy donors, represent a promising solution to these obstacles. These "off-the-shelf" therapies aim to reduce the complexity and cost of CAR-T production. Despite exciting advancements in genome-editing technologies and promising clinical trial data, significant challenges remain, including graft-

Bacterial Involvement in Progression and Metastasis of Adenocarcinoma of the Stomach.

Gastric cancer metastasis is a process in which the tumor microenvironment may carry significant influence. Helicobacter pylori (H. pylori) infection is well-established as a contributor to gastric carcinoma. However, the role that these bacteria and others may play in gastric carcinoma metastasis is a current focus of study. A review of the literature was conducted to elucidate the process by which gastric adenocarcinoma metastasizes, including its ability to utilize both the lymphatic system and the venous system to disseminate. Studies that investigate the tumor microenvironment at both the

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… Helicobacter Pylori-Induced Heparanase Promotes H. pylori Colonization and Gastritis. Front. Immunol. 2021;12:2352. doi: 10.3389/fimmu.2021.675747. 65. Narayanan M., Reddy K.M., Marsicano E. Peptic Ulcer Disease and Helicobacter Pylori Infection. Mo. Med. 2018;115:219–224. 66. …

Endogenous immune recruitment in glioblastoma CAR T therapy: cytokine, myeloid, and chemokine circuitry.

BackgroundGlioblastoma (GBM) has remained relatively unresponsive to immunotherapy, with scattered durable responses reported in early CAR T-cell studies, but without clear benefit at the population level. The major challenge for GBM has been its heterogeneous nature with a significantly immunosuppressive microenvironment that is predominantly composed of myeloid cells, inhibiting T-cell infiltration, function, and providing a rapid pathway for adaptive resistance. The focus of this review is to reposition GBM CAR T-cell therapy as a systems-level issue, turning localized CAR T-cell cytotoxici

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… Caruana I, Savoldo B, Hoyos V et al (2015) Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med 21:524–529 47. …

Novel Cellular Therapies for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Most patients present with advanced disease, and current gold-standard management using tyrosine kinase inhibitors or immune checkpoint inhibitors (ICIs) offers modest clinical benefit. Cellular immune therapies targeting HCC are currently being tested in the laboratory and in clinical trials. Here, we review the landscape of cellular immunotherapy for HCC, defining antigenic targets, outlining the range of cell therapy products being applied in HCC (such as CAR-T and TCR-T), and exploring how advanc

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… Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes Nat. Med. 2015 21 524 529 10.1038/nm.3833 25849134 PMC4425589 124. Zou B. Liu X. Zhang B. Gong Y. Cai C. Li P. Chen J. Xing S. Chen J. Peng S. …