Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Miriam Gross-Cohen ¹ Sari Feld ¹ Ilana Doweck ² Gera Neufeld ¹ Peleg Hasson ³ Gil Arvatz ¹ Uri Barash ¹ Inna Naroditsky ⁴ Neta Ilan ¹ Israel Vlodavsky ¹

¹Cancer and vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Israel
²Department of Otolaryngology, Head and Neck Surgery, Carmel Medical Center, Israel
³Department of Cell Biology, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Israel
⁴Department of Pathology, Rambam Health Care Campus, Israel

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate (HS) side chains of proteoglycans, activity that is highly implicated in tumor metastasis and angiogenesis. Heparanase 2 (Hpa2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. In head and neck cancer patients, Hpa2 expression was markedly elevated correlating with prolonged time to disease recurrence and inversely correlating with tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions as a tumor suppressor. The molecular mechanism associated with favorable prognosis following Hpa2 induction is unclear.

Here, we provide evidence that Hpa2 over expression in head and neck cancer cells markedly reduces tumor growth. Restrained tumor growth was associated with a prominent decrease in tumor vascularity (blood and lymph vessels), likely due to reduced Id1 expression, a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation. Hpa2 also induces the expression of lysyl oxidase (LOX), an enzyme that crosslinks collagen and elastin, thereby affecting ECM remodeling and tissue fibrosis. Expression of lysyl oxidase-like 2 (LOXL2) was not induced but assumed nuclear localization in tumor xenografts produced by Hpa2 over expressing cells.

Notably, heparanase enzymatic activity was not impaired in cells over expressing Hpa2, suggesting that reduced tumor growth is not due to heparanase regulation. Moreover, growth of tumor xenografts produced by Hpa2 over-expressing cells was not affected by a monoclonal antibody that targets the heparin binding domain of Hpa2, implying that Hpa2 functions in heparanase-, and HS-independent manner.