Dysregulation of the Tumor Microenvironment in Hepatocellular Carcinoma

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The stromal changes underlying the development and progression of HCC are important but incompletely understood. Chronic inflammation resulting in liver cirrhosis is the most important risk factor for the development of HCC, hence changes in the stromal microenvironment must be important in the development and progression of HCC. Cirrhosis is characterized by activation and proliferation of stellate cells/pericytes and consequent expansion of the extracellular matrix (ECM). Stellate cell activation is dependent on signaling by platelet-derived growth factor (PDGF), a heparin-binding growth factor, and transforming growth factor-¿ (TGF-¿) which is stored in the ECM bound to latent TGF-¿ binding proteins and is presented to the TGF¿R2 activating receptor by the heparan sulfate proteoglycan (HSPG) coreceptor TGF¿R3. In response to PDGF, pericytes produce FGF, HGF, and VEGF, which, in turn, can act on tumor cells and endothelial cells, creating positive feedback loops that drive carcinogenesis. We have shown that the recently identified heparin-degrading endosulfatase, SULF2, is associated with tumor recurrence and worse prognosis of human HCC and promotes the growth of HCC xenografts in nude mice; in contrast, the related sulfatase SULF1 has a tumor suppressor effect. SULF2 is secreted by tumor cells into the ECM and desulfates HSPGs at the 6-O position of glucosamine. 6-O sulfation is required for binding of heparin-binding growth factors to HSPGs. By desulfating HSPGs, SULF2 decreases the binding of HSPGs to growth factors, releases them from the cell surface and ECM, and makes them available for binding to their receptors. We hypothesize that SULF2 releases PDGF and TGF-¿ and promotes stellate cell activation, angiogenesis and tumor growth. In Specific Aim 1 we will test the hypothesis that SULF2 releases PDGF and TGF-¿ from storage sites by desulfating HSPGs in the ECM and at the stellate cell surface. In Specific Aim 2 we will test the hypothesis that expression of SULF2 by HCC tumor cells enhances stellate cell activation by PDGF and TGF-¿ and stimulates tumor growth. In Specific Aim 3, we will test the hypothesis that SULF1 antagonizes the effects of SULF2 on PDGF- and TGF-¿-mediated stellate cell activation. Successful completion of these studies will provide novel insight into the role of tumor-stromal interactions in the molecular pathogenesis of HCC, and may lead to the development of rational targeted therapeutic strategies against HCC. PUBLIC HEALTH RELEVANCE: The rates of development of primary liver cancer in the US have doubled over the past 20 years, primarily due to increases in hepatitis C virus infection rates. Liver cancer can be treated by surgery or transplantation if detected early, but is otherwise rapidly fatal because there are no effective chemotherapy treatments for advanced disease. This study will investigate the function of recently discovered sulfatase enzymes that enhance growth of liver cancers, with the goal of developing effective treatments for this devastating disease.