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Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation.

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient-oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease; sleep and control of breathing; and the application of

Relationship between circulating syndecan-1 levels (CD138s) and serum free light chains in monoclonal gammopathies.

BackgroundMonoclonal gammopathies encompass a wide range of diseases characterized by the monoclonal expansion of a B-cell clone. Despite emerging therapeutic strategies, chances of survival of patients who are affected are still scarce, which implies that new tools are necessary not only for the diagnosis but also for the follow-up of patients affected by such diseases. In this context, the use of free light chains (FLCs) has been incorporated into many guidelines. Likewise, tumor microenvironment is consistently gaining importance as role player in tumor pathogenesis. Specifically, Syndecan-

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… Cell surface CD138 is processed by a specific heparanase endo-β-D-glucuronidase consequently releasing the extracellular, bioactive portion (ectodomain) of the molecule [ 29 ]. … For this reason, the CD138/heparanase axis is consistently gaining attention as therapeutic target due to its importance in driving cancer and in determining tumor aggressiveness [ 36 , 37 ]. …

Targeted therapy for multiple myeloma: an overview on CD138-based strategies.

Multiple myeloma (MM) is an incurable hematological disease characterized by the uncontrolled growth of plasma cells primarily in the bone marrow. Although its treatment consists of the administration of combined therapy regimens mainly based on immunomodulators and proteosome inhibitors, MM remains incurable, and most patients suffer from relapsed/refractory disease with poor prognosis and survival. The robust results achieved by immunotherapy targeting MM-associated antigens CD38 and CD319 (also known as SLAMF7) have drawn attention to the development of new immune-based strategies and diffe

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… In addition, heparanase (HPSE), an endoglycosidase that acts within the ECM to trim HS chains and generate specific short fragments by exposing the core protein for cleavage by MMPs, is largely involved in CD138 shedding and is severely implicated in tumor angiogenesis, growth and metastasis ( 116 – … Heparanase inhibitor HPSE is the main enzyme responsible for extracellular HS degradation and its expression is significantly increased in aggressive cancers, facilitating tumor progression through metastatic dissemination ( 122 , 197 ). …

Multiple Myeloma Cell-Derived Exosomes: Implications on Tumorigenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological disease that is still not curable. The bone marrow milieu, with cellular and non-cellular elements, participate in the creation of a pro-tumoral environment enhancing growth and survival of MM plasma cells. Exosomes are vesicles oscillating in dimension between 50 nm and 100 nm in size that can be released by various cells and contribute to the pathogenesis and progression of MM. Exosomes enclose proteins, cytokines, lipids, microRNAs, long noncoding RNAs, and circular RNAs able to regulate interactions between MM plasma cells and adjacent cells. Throug

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… A further system able to induce chemoresistance could be Heparanase. It is an endo-β-D-glucuronidase that operates cleaving heparan sulfate chains. … An experiment explained the role of heparinase that revealed a direct correlation between Bz sensitivity, heparanase, and miRNA-1252-5p expression. …

Program-Abstracts

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… in Colitis Associated Cancer 09:46 Karen Hunter , New York, NY, USA The Role of Heparanase in Promoting Multistage Pancreatic Islet Tumorigenesis 09:58 Margarida Bernardo, Detroit, MI, USA Maspin Restores Redifferentiation of Prostate Cancer Cells in Collagen I 10:10 Lingtao Wu , Los Angeles, CA … Muschel , Oxford, UK 11:30 Dario Marchetti , Houston, TX, USA Heparanase: A Critical Determinant of Breast Cancer Metastasis to Brain 11:50 Adriana Haimovitz-Friedman , New York, NY, USA A Ceramide Rheostat Balances Angiogenesis and Anti-angiogenesis 12:10 Yoav Leiser , Haifa, Israel Heparanase …

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases.

PurposeIn 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121-167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper.MethodsA literature search mainly focusing on the role of the glycocalyx in the

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… That the degradation of GCX in sepsis prevails over increased synthesis of glycans, major components of GCX, suggests an enhanced enzymatic degradation, which is carried out by sheddases, including a disintegrin and metalloproteinases (ADAMs), MMPs, heparanases and hyaluronidases. 63 While ADAM 10 is … Heparanase mediated shedding of HS on SDC1 enables growth factor in the tumor microenvironment to access receptors and activate cell signaling that fosters tumor growth and progression. …

Malignant mesothelioma tumours: molecular pathogenesis, diagnosis, and therapies accompanying clinical studies.

The pathetic malignant mesothelioma (MM) is a extremely uncommon and confrontational tumor that evolves in the mesothelium layer of the pleural cavities (inner lining- visceral pleura and outer lining- parietal pleura), peritoneum, pericardium, and tunica vaginalis and is highly resistant to standard treatments. In mesothelioma, the predominant pattern of lesions is a loss of genes that limit tumour growth. Despite the worldwide ban on the manufacture and supply of asbestos, the prevalence of mesothelioma continues to increase. Mesothelioma presents and behaves in a variety of ways, making dia

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… The main enzyme for intercellular heparan sulfate degradation is heparanase, and malignant tumors exhibit a dramatically increased expression of this enzyme ( 123 ). … Heparanase impact on tumorigenesis was observed in pre-clinical in-vivo murine prototypes of MPM in sensitivity to heparanase-inhibiting drugs and heparanase gene ablation. …

Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors.

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc

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… Heparanase, also recognized as HPSE or HPA1, is another tGLI1 target gene that has been more extensively researched as an antiangiogenic, anti-cancer drug target [ 141 ]. … Several classes of heparanase inhibitors have been studied, the most characterized of which include the heparan sulfate mimetics PI-88 and PG545. …

Structure, function, and pathology of PHF23.

Plant Homeodomain Finger Protein 23 (PHF23) is a member of the Plant Homeodomain (PHD) finger protein family and has been extensively reported since its discovery. Numerous studies have demonstrated that PHF23 plays a crucial role in various biological processes, such as gene expression regulation, autophagy, and tumorigenesis. Additionally, PHF23 is associated with various diseases including various malignancies, osteoarthritis, and tuberculosis, all of which currently lack effective and targeted treatment options. Therefore, this review systematically summarizes the existing literature on PH

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… Notably, the role of PHF23 in promoting tumor metastasis is similar to the function of heparanase in tumor invasion. … This suggests that PHF23 may have a potential connection with heparanase, thereby influencing the development of NSCLC. …

Molecular Impact of the Tumor Microenvironment on Multiple Myeloma Dissemination and Extramedullary Disease.

Multiple myeloma (MM) is the most common malignant monoclonal disease of plasma cells. Aside from classical chemotherapy and glucocorticoids, proteasome inhibitors, immunomodulatory agents and monoclonal antibodies are used in the current treatment scheme of MM. The tumor microenvironment (TME) plays a fundamental role in the development and progression of numerous solid and non-solid cancer entities. In MM, the survival and expansion of malignant plasma cell clones heavily depends on various direct and indirect signaling pathways provided by the surrounding bone marrow (BM) niche. In a number

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… Treatment with bortezomib and melphalan induces secretion of exosomes containing heparanase that results in degradation of ECM; thus, facilitating myeloma invasion ( 93 ). The TME provides a complex network of molecules that can affect the phenotype of PCs. … Chemotherapy Induces Secretion of Exosomes Loaded With Heparanase That Degrades Extracellular Matrix and Impacts Tumor and Host Cell Behavior. Matrix Biol (2018) 65:104–18. doi: 10.1016/j.matbio.2017.09.001 …

Risk Prediction and New Prophylaxis Strategies for Thromboembolism in Cancer.

Venous thromboembolism (VTE) is a compelling challenge across all phases of cancer care as it may result in treatment delays, impaired quality of life (QoL), and increased mortality [...].

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… Heparanase, indeed, is capable of degrading heparin and low-molecular-weight heparin (LMWH), possibly resulting in neutralization of the anticoagulant properties of these molecules [ 9 ]. … Interestingly, heparanase was found to be highly expressed in pancreatic, gastric, and lung cancers, which are all correlated with a higher risk of thrombosis compared to other tumor types [ 10 ]. …

Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives.

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles

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… In particular, it was shown that the surface of chemoexosomes is enriched with high levels of heparanase, which is responsible for the degradation of heparan sulphate in the extracellular matrix. … Moreover, it has been highlighted a strong correlation between heparanase and miRNA-1252-5p expression in MM cells treated with Bortezomib. …

Recent Progress of Exosomes in Multiple Myeloma: Pathogenesis, Diagnosis, Prognosis and Therapeutic Strategies.

Multiple myeloma (MM) is a hematological malignancy that is still incurable. The bone marrow microenvironment (BMM), with cellular and non-cellular components, can create a favorable environment for the survival, proliferation and migration of MM cells, which is the main reason for the failure of MM therapies. Many studies have demonstrated that exosomes play an important role in the tumor-supportive BMM. Exosomes are nanoscale vesicles that can be released by various cells. Some exosomes contribute to the pathogenesis and progression of MM. MM-derived exosomes act on different cells in the BM

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… The surface of a chemoexosome is enriched with heparanase. When these chemoexosomes are exposed to other MM cells, heparanase can be transferred to other MM cells. … Heparanase: A Dynamic Promoter of Myeloma Progression. Adv. Exp. Med. Biol. 2020;1221:331–349. doi: 10.1007/978-3-030-34521-1_12. 53. Chauhan D., Uchiyama H., Akbarali Y., Urashima M., Yamamoto K., Libermann T.A., Anderson K.C. …

Mesenchymal stem cells lineage and their role in disease development.

BackgroundMesenchymal stem cells (MSCs) are widely dispersed in vivo and are isolated from several tissues, including bone marrow, heart, body fluids, skin, and perinatal tissues. Bone marrow MSCs have a multidirectional differentiation potential, which can be induced to differentiate the medium in a specific direction or by adding specific regulatory factors. MSCs repair damaged tissues through lineage differentiation, and the ex vivo transplantation of bone marrow MSCs can heal injured sites. MSCs have different propensities for lineage differentiation and pathological evolution for differen

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… Heparanase enhances osteoclastogenesis and bone loss and shifts the differentiation potential of MSCs from osteoblastogenesis to adipogenesis (Ruan et al. 2013 ). … Function of heparanase in prostate tumorigenesis: potential for therapy. Clin Cancer Res. 2008;14(3):668–76. Li X, Bai J, Ji X, Li R, Xuan Y, Wang Y. …

The link between bone-derived factors osteocalcin, fibroblast growth factor 23, sclerostin, lipocalin 2 and tumor bone metastasis.

The skeleton is the third most common site of metastatic disease, which causes serious bone complications and short-term prognosis in cancer patients. Prostate and breast cancers are responsible for the majority of bone metastasis, resulting in osteolytic or osteoblastic lesions. The crosstalk between bone cells and their interactions with tumor cells are important in the development of lesions. Recently, both preclinical and clinical studies documented the clinical relevance of bone-derived factors, including osteocalcin (OC) and its undercarboxylated form (ucOC), fibroblast growth factor 23

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… -6, bone morphogenetic protein 6; CBFβ, core binding factor beta; CTx, C-terminal telopeptide of type I collagen; EGR1, early growth response factor 1; ERK, extracellular signal-regulated kinase; FGF23, fibroblast growth factor 23; GPRC6A, G protein-coupled receptor family C group 6 member A; HPSE, heparanase … FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells. Oncotarget (2015) 6:19647–60. doi: 10.18632/oncotarget.3794 46. Lee EK, Martinez MCR, Blakely K, Santos KD, Hoang VC, Chow A, et al. …

Increased Cytoplasmic CD138 Expression Is Associated with Aggressive Characteristics in Prostate Cancer and Is an Independent Predictor for Biochemical Recurrence.

Syndecan-1 (CD138) is a transmembrane proteoglycan expressed in various normal and malignant tissues. It is of interest due to a possible prognostic effect in tumors and its role as a target for the antibody-drug conjugate indatuximab ravtansine. Here, we analyzed 17,747 prostate cancers by immunohistochemistry. Membranous and cytoplasmic CD138 staining was separately recorded. In normal prostate glands, CD138 staining was limited to basal cells. In cancers, membranous CD138 positivity was seen in 19.6% and cytoplasmic CD138 staining in 11.2% of 12,851 interpretable cases. A comparison with cl

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… It appears possible that the extracellular enzyme heparanase (HPSE) plays a role in CD138 shedding by inducing proteolytic cleavage with increasing metastatic potential as result. … Heparanase, which also contributes to de novo synthesis of CD138, has been shown to be overexpressed in several tumors, also in prostate cancer (summarized in [ 20 ]). …

A Challenge to Aging Society by microRNA in Extracellular Vesicles: microRNA in Extracellular Vesicles as Promising Biomarkers and Novel Therapeutic Targets in Multiple Myeloma.

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells and is the second most common hematological cancer. MM frequently occurs in the elderly population with the median age as the middle sixties. Over the last 10 years, the prognosis of MM has been dramatically improved by new therapeutic drugs; however, MM is still incurable. The pathogenesis of MM is still unclear, thus greater understanding of the molecular mechanisms of MM malignancy is desirable. Recently, microRNAs (miRNAs) were shown to modulate the expression of genes critical for MM pathogenesis. In addition,

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… Moreover, heparan sulfate proteoglycans function as internalizing receptors of cancer cell-derived EVs, and their modification through antitumor action inhibits MM cell growth and angiogenesis via disruption of the heparanase/syndecan-1 (CD138) axis [ 30 ]. … SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin. Cancer Res. 2011;17:1382–1393. doi: 10.1158/1078-0432.CCR-10-2476. 31. Cheng Q., Li X., Liu J., Ye Q., Chen Y., Tan S., Liu J. …

Targeting Tumor Microenvironment for Cancer Therapy.

Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response

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… This drug can inhibit heparanase activity, the expression of which is induced by macrophages infiltrating pre-neoplastic/neoplastic lesions [ 102 ]. … SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin. Cancer Res. 2011;17:1382–1393. doi: 10.1158/1078-0432.CCR-10-2476. 32. …

Cancer-Associated Thrombosis: Pathophysiology, Laboratory Assessment, and Current Guidelines.

Dysregulated hemostasis in cancer patients is associated with various clinical conditions, from thromboembolic complications to disseminated intravascular coagulation. Despite the well-established association between cancer and thromboembolic complications, the mechanisms involved are not completely elucidated. There are several predisposing factors in cancer for increased thrombus generation, such as immobilization and chemotherapy. The term cancer-associated thrombosis (CAT) has been introduced to describe the close bidirectional relationship between cancer and thromboembolic events. Convent

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… Other procoagulant molecules expressed by tumor cells include heparanase, cancer procoagulant (CP), and podoplanin (PDP). … Heparanase is an enzyme that can upregulate the expression of TF through the disassociation of TFPI, and tumor cells that express heparanase are considered to have increased metastatic potential [ 1 , 28 , 30 ]. …