Heparan sulfate (HS) proteoglycans play a key role in the self-assembly, insolubility and barrier properties of the extracellular matrix (ECM). Cleavage of HS therefore affects the integrity of tissues and hence normal and pathological phenomena involving cell migration and response to changes in the ECM. Mammalian heparanase, endo-beta-D-glucuronidase, first cloned and characterized in our laboratory, is synthesized as a latent 65 kDa protein that is processed into a highly active 50 kDa enzyme. Heparanase is preferentially expressed in human tumors and its overexpression in tumor cells confers an invasive phenotype in experimental animals. Heparanase also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Enhanced heparanase expression correlates with metastatic potential, tumor vascularity and reduced postoperative survival of cancer patients. These observations, the anti-cancerous effect of heparanase-inhibiting molecules, and the unexpected identification of a predominant functional heparanase suggest that the enzyme is a promising target for drug development. Given the potential tissue damage that could result from inadvertent cleavage of HS, tight regulation is essential. Of particular interest is the significance of cell surface expression and secretion of heparanase, its proteolytic processing, cellular uptake, and effects on cell adhesion, migration, metastasis, and angiogenesis. We propose to investigate the involvement of heparanase in cancer progression, emphasizing regulatory aspects, normal functions, and non-enzymatic activities of the molecule, as well as approaches to efficiently inhibit heparanase expression and activity. Specifically, we will (I) investigate the regulation of heparanase promoter activity and characterize the proteolytic activity and molecular interactions involved in processing and activation of latent heparanase; (II) generate and characterize heparanase transgenic and knockout mice and elucidate heparanase normal functions and interaction with cellular proteins; (III) study involvement of heparanase, expressed by the tumor and its microenvironment, in tumor growth, angiogenesis, and metastasis; and (IV) develop inhibitors of heparanase gene expression and enzymatic activity. Efficient inhibitors will be tested in experimental models of tumor progression. The proposed research stems from studies performed since the cloning of the heparanase gene, and availability of molecular probes (i.e., recombinant latent and active heparanases; intracellular, secreted and point mutated species of heparanase, anti-heparanase antibodies), assay systems (i.e., MRI analysis of vascular density and functionality) and animal models to elucidate causal involvement of heparanase in cancer progression. It is through understanding of the enzyme's physiology and regulation that adequate heparanase-inhibiting strategies can be designed and applied in the treatment of cancer and possibly other disorders involving HS and heparanase.
| Weissmann, Marina; Arvatz, Gil; Horowitz, Netanel et al. (2016) Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proc Natl Acad Sci U S A 113:704-9 |
| Gross-Cohen, Miriam; Feld, Sari; Doweck, Ilana et al. (2016) Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth. Cancer Res 76:2791-801 |
| Gross-Cohen, Miriam; Feld, Sari; Naroditsky, Inna et al. (2016) Heparanase 2 expression inversely correlates with bladder carcinoma grade and stage. Oncotarget 7:22556-65 |
| Kovalchuk Ben-Zaken, O; Nissan, I; Tzaban, S et al. (2015) Transgenic over-expression of mammalian heparanase delays prion disease onset and progression. Biochem Biophys Res Commun 464:698-704 |
| Ilan, Neta; Shteingauz, Anna; Vlodavsky, Israel (2015) Function from within: Autophagy induction by HPSE/heparanase--new possibilities for intervention. Autophagy 11:2387-9 |
| Shteingauz, Anna; Boyango, Ilanit; Naroditsky, Inna et al. (2015) Heparanase Enhances Tumor Growth and Chemoresistance by Promoting Autophagy. Cancer Res 75:3946-57 |
| Lapidot, Moshe; Barash, Uri; Zohar, Yaniv et al. (2015) Involvement of Heparanase in Empyema: Implication for Novel Therapeutic Approaches. J Clin Cell Immunol 6: |
| Boyango, Ilanit; Barash, Uri; Naroditsky, Inna et al. (2014) Heparanase cooperates with Ras to drive breast and skin tumorigenesis. Cancer Res 74:4504-14 |
| Hermano, Esther; Meirovitz, Amichay; Meir, Karen et al. (2014) Macrophage polarization in pancreatic carcinoma: role of heparanase enzyme. J Natl Cancer Inst 106: |
| Lerner, Immanuel; Zcharia, Eyal; Neuman, Tzahi et al. (2014) Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice. Cell Mol Life Sci 71:2347-2357 |
Showing the most recent 10 out of 103 publications
