title: Heparanase cooperates with Ras to drive breast and skin tumorigenesis.
abstract: Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.
authors: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Ilanit
authors: I
authors: Boyango
authors: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Uri
authors: U
authors: Barash
authors: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors: Inna
authors: I
authors: Naroditsky
authors: Department of Medical Biochemistry and Microbiology, University of Uppsala, Uppsala, Sweden.
authors: Jin-Ping
authors: JP
authors: Li
authors: Progen Pharmaceuticals, Brisbane, Queensland, Australia.
authors: Edward
authors: E
authors: Hammond
authors: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors: Neta
authors: N
authors: Ilan
authors: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. vlodavsk@mail.huji.ac.il.
authors: Israel
authors: I
authors: Vlodavsky
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D005966:Glucuronidase / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D010766:Phosphorylation; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase