Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy

Shteingauz, Anna; Boyango, Ilanit; Naroditsky, Inna; Hammond, Edward; Gruber, Maayan; Doweck, Ilana; Ilan, Neta; Vlodavsky, Israël

doi:10.1158/0008-5472.can-15-0037

Cited by 140 publications

(168 citation statements)

References 53 publications

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“…96 Lysosomal heparanase fuses with autophagosomes contributing to the cellular control of autophagy. Tumor cells that overexpress heparanase were found to have increased levels of autophagy, which promoted tumor growth and chemotherapy resistance.…”

Section: The Role Of Heparanase In Cancer Biologymentioning

confidence: 99%

“…Tumor cells that overexpress heparanase were found to have increased levels of autophagy, which promoted tumor growth and chemotherapy resistance. 96 Mechanistically, autophagy induction by heparanase occurs through the mammalian target of rapamycin complex 1 pathway (MTORC1). Decreased phosphorylation of RPS6KB/p70 S6-kinase, a MTORC1 substrate, was found in cells over expressing heparanase indicating increased autophagy.…”

Section: The Role Of Heparanase In Cancer Biologymentioning

confidence: 99%

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Mechanisms of heparanase inhibitors in cancer therapy

Heyman

Yang

2016

Experimental Hematology

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Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains contributing to break down of the extracellular matrix. Increased expression of heparanase has been found in numerous malignancies, and is associated with a poor prognosis. It has generated significant interest as a potential anti-neoplastic target because of the multiple roles it plays in tumor growth and metastasis. The pro-tumorigenic effects of heparanase are enhanced by the release of HS side chains, with subsequent increase in bioactive fragments and increased cytokine levels; both promoting tumor invasion, angiogenesis and metastasis. Preclinical experiments have shown heparanase inhibitors to substantially reduce tumor growth and metastasis leading to clinical trials with heparan sulfate mimetics. In this review we will examine heparanase’s role in tumor biology, its interaction with heparan surface proteoglycans, specifically syndecan-1; as well as the mechanism of action for heparanase inhibitors developed as anti-neoplastic therapeutics.

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Section: The Role Of Heparanase In Cancer Biologymentioning

confidence: 99%

Section: The Role Of Heparanase In Cancer Biologymentioning

confidence: 99%

Mechanisms of heparanase inhibitors in cancer therapy

Heyman

Yang

2016

Experimental Hematology

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“…As such, Perlecan’s HS specified bioactivities can be suppressed by the action of heparanase that degrades HS [189]. On an interesting note, exogenous heparanase and heparanase overexpression increase autophagy by downregulating signaling from the negative regulator mTORC1 [192]. While the colocalization of intracellular heparanase, autophagosome and lysosomes correlates with enhanced autophagy, one cannot rule out the possibility that the degradation of extracellular HS chains and other HSPG (heparan sulfate proteoglycans) could liberate ligands for autophagy activation.…”

Section: Autophagy Regulation By the Extracellular Matrix (Ecm): “Outmentioning

confidence: 99%

Molecular Functions of Glycoconjugates in Autophagy

Fahie

Zachara

2016

Journal of Molecular Biology

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Glycoconjugates, glycans, carbohydrates, and sugars: these terms encompass a class of biomolecules that are diverse in both form and function ranging from free oligosaccharides, glycoproteins and proteoglycans, to glycolipids that make up a complex glycan-code that impacts normal physiology and disease. Recent data suggests that one mechanism by which glycoconjugates impact physiology is through the regulation of the process of autophagy. Autophagy is a degradative pathway necessary for differentiation, organism development, and the maintenance of cell and tissue homeostasis. In this review, we will highlight what is known about the regulation of autophagy by glycoconjugates focusing on signaling mechanisms from the extracellular surface and the regulatory roles of intracellular glycans. Glycan signaling from the extracellular matrix converges on “master” regulators of autophagy including AMPK and mTORC1, thus impacting their localization, activity and/or expression. Within the intracellular milieu, gangliosides are constituents of the autophagosome membrane, a subset of proteins composing the autophagic machinery are regulated by glycosylation, and oligosaccharide exposure in the cytosol triggers an autophagic response. The examples discussed provide some mechanistic insights into glycan regulation of autophagy and reveals areas for future investigation.

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“…8 Recent studies emphasize the involvement of heparanase in exosome formation, 9 activation of the immune system, 10,11 autophagy 12 and chemo-resistance, 12,13 further highlighting its significance in mediating the crosstalk between tumor cells and the tumor microenvironment and in dictating the tumor response to stress and host factors. The protumorigenic effect of heparanase is attributed primarily to its HS degrading activity, facilitating cell invasion and 'priming' the tumor microenvironment.…”

Section: Heparanase and Cancermentioning

confidence: 99%

“…2,6,7 A causal role of heparanase in tumor metastasis was demonstrated by the increased lung, liver and bone colonization of cancer cells following over-expression of the heparanase gene, and by a marked decrease in the metastatic potential of cells subjected to heparanase gene silencing. 8 Recent studies emphasize the involvement of heparanase in exosome formation, 9 activation of the immune system, 10,11 autophagy 12 and chemo-resistance, 12,13 further highlighting its significance in mediating the crosstalk between tumor cells and the tumor microenvironment and in dictating the tumor response to stress and host factors. The protumorigenic effect of heparanase is attributed primarily to its HS degrading activity, facilitating cell invasion and 'priming' the tumor microenvironment.…”

Section: Heparanase and Cancermentioning

confidence: 99%

Heparanase and cancer progression: New directions, new promises

Arvatz¹,

Weissmann²,

Ilan³

et al. 2016

Human Vaccines & Immunotherapeutics

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor progression. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulated heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Notably, heparanase is ranked among the most frequently recognized tumor antigens in patients with pancreatic, colorectal or breast cancer, favoring heparanase-based immunotherapy. Development of heparanase inhibitors focused on carbohydrate-based compounds of which 4 are being evaluated in clinical trials for various types of cancer, including myeloma, pancreatic carcinoma and hepatocellular carcinoma. Owing to their heparin-like nature, these compounds may exert off target effects. Newly generated heparanase neutralizing monoclonal antibodies profoundly attenuated myeloma and lymphoma tumor growth and dissemination in preclinical models, likely by targeting heparanase in the tumor microenvironment. KEYWORDSHeparanase; immunotherapy; lymphoma; neutralizing monoclonal antibody; tumor microenvironment Heparanase and cancerHeparan sulfate (HS) proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of tissues.1 The HS chains bind to and assemble ECM proteins, thus playing important roles in ECM integrity, barrier function and cell-ECM interactions.1 HSPGs not only provide a storage depot for heparin-binding molecules (i.e., growth factors, chemokines, enzymes) in the tumor microenvironment, but also decisively regulate their accessibility, function and mode of action. It is therefore not surprising that a HS degrading enzyme (i.e., heparanase) is critically involved in tumor growth, angiogenesis and metastasis. Mammalian cells express a single dominant functional heparanase, an endoglycosidase that cleaves HS, leading to disassembly of the ECM and release of HS-bound bioactive molecules, thereby affecting tumor progression, angiogenesis and inflammation.2-4 The heparanase mRNA encodes a 65 kDa pro-enzyme that is cleaved by cathepsin L into 8 and 50 kDa subunits that non-covalently associate to form the active enzyme.5 Heparanase is up-regulated in essentially all human tumors examined, most often associating with reduced patients' survival post operation, increased tumor metastasis and higher vessel density.2,6,7 A causal role of heparanase in tumor metastasis was demonstrated by the increased lung, liver and bone colonization of cancer cells following over-expression of the heparanase gene, and by a marked decrease in the metastatic potential of cells s...

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Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy

Cited by 140 publications

References 53 publications

Mechanisms of heparanase inhibitors in cancer therapy

Mechanisms of heparanase inhibitors in cancer therapy

Molecular Functions of Glycoconjugates in Autophagy

Heparanase and cancer progression: New directions, new promises

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