title: Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy.
abstract: Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity implicated in tumor inflammation, angiogenesis, and metastasis. Heparanase is secreted as a latent enzyme that is internalized and subjected to proteolytic processing and activation in lysosomes. Its role under normal conditions has yet to be understood. Here, we provide evidence that heparanase resides within autophagosomes, where studies in heparanase-deficient or transgenic mice established its contributions to autophagy. The protumorigenic properties of heparanase were found to be mediated, in part, by its proautophagic function, as demonstrated in tumor xenograft models of human cancer and through use of inhibitors of the lysosome (chloroquine) and heparanase (PG545), both alone and in combination. Notably, heparanase-overexpressing cells were more resistant to stress and chemotherapy in a manner associated with increased autophagy, effects that were reversed by chloroquine treatment. Collectively, our results establish a role for heparanase in modulating autophagy in normal and malignant cells, thereby conferring growth advantages under stress as well as resistance to chemotherapy. Cancer Res; 75(18); 3946-57. ©2015 AACR.
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Shteingauz
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Ilanit
authors.initials: I
authors.lastname: Boyango
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Naroditsky
authors.affiliation: Progen Pharmaceuticals, Brisbane, Queensland, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Gruber
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Haifa, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Doweck
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. Vlodavsk@mail.huji.ac.il.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000596:Amino Acids / Q000172:deficiency; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000502:physiology*; D002277:Carcinoma / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005910:Glioma / Q000473:pathology; D005966:Glucuronidase / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D010588:Phagosomes / Q000201:enzymology; D010610:Pharyngeal Neoplasms / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000378:metabolism; D051381:Rats; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D000099175:Heparanase
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D002738:Chloroquine; D002945:Cisplatin; D005966:Glucuronidase; D000076222:Mechanistic Target of Rapamycin Complex 1; D008563:Membrane Lipids; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D010714:Phosphatidylethanolamines; D058570:TOR Serine-Threonine Kinases; D000099175:Heparanase