Highly Effective Heparanase-Based Therapy for Mesothelioma

Malignant mesothelioma is a highly aggressive form of cancer that develops from cells of the mesothelium - the protective lining that covers many internal organs of the body. It has a poor prognosis because of the lack of markers for early diagnosis, and resistance to conventional therapies, underscoring the need for novel treatments. Mesothelioma tumors express high levels of heparanase, the sole mammalian endoglycosidase degrading heparan sulfate (HS) side chains of HS-proteoglycans in the extracellular matrix (ECM) and cell surface. Heparanase activity facilitates cell invasion and releases growth- and angiogenesis-promoting factors that are stored as a complex with HS in the ECM and tumor microenvironment. We demonstrate that heparanase is expressed and enzymatically active in several pleural mesothelioma cell lines. Moreover, AE17 mouse mesothelioma cells developed significantly smaller tumors when inoculated subcutaneously into heparanase knockout (Hpa-KO) vs control mice, emphasizing the contribution of the host microenvironment. Immunostaining revealed lower proliferation and higher apoptosis rates in tumors developed in Hpa-KO mice associating with reduced c-Jun phosphorylation and VEGF expression. Likewise, Heparanase gene silencing diminished cell invasion in vitro and tumor xenograft growth in-vivo. In addition, heparanase inhibitor (PG545) attenuated cell invasion and anchorage independent growth of mesothelioma cell lines in vitro, and reduced mesothelioma tumor xenografts development by inhibiting angiogenesis and Akt phosphorylation. Notably, PG545 significantly increased the survival of mice implanted with mesothelioma cells, beyond conventional chemotherapy (cisplatin). In conclusion, heparanase plays an important role in mesothelioma tumor progression, thus encouraging further development of heparanase inhibitors (e.g. PG545) for this incurable malignancy.