Dysregulation of the Tumor Microenvironment in Hepatocellular Carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是全球第三大癌症死亡原因。 HCC发生和发展的基础基质变化很重要，但尚未完全了解。 导致肝硬化的慢性炎症是HCC发展的最重要的危险因素，因此基质微环境的变化在HCC的发展和进展中一定是重要的。 肝硬化的特征在于星状细胞/周细胞的活化和增殖以及随之而来的细胞外基质（ECM）的扩增。 星状细胞活化依赖于血小板衍生生长因子（PDGF）、肝素结合生长因子和转化生长因子-<$（TGF-<$）的信号传导，转化生长因子-<$储存在ECM中，与潜在的TGF-<$结合蛋白结合，并通过硫酸乙酰肝素蛋白聚糖（HSPG）辅助受体TGF <$R3呈递给TGF <$R2活化受体。 作为对PDGF的响应，周细胞产生FGF、HGF和VEGF，其反过来可以作用于肿瘤细胞和内皮细胞，产生驱动癌发生的正反馈回路。 我们已经表明，最近发现的肝素降解硫酸酯酶，SULF 2，与肿瘤复发和预后不良的人肝癌，并促进肝癌裸鼠移植瘤的生长，相比之下，相关的硫酸酯酶SULF 1具有肿瘤抑制作用。 SULF 2由肿瘤细胞分泌到ECM中，并在葡糖胺的6-O位上使HSPG变性。 肝素结合生长因子与HSPG的结合需要6-O硫酸化。 通过使HSPG变性，SULF 2减少HSPG与生长因子的结合，将其从细胞表面和ECM释放，并使其可用于结合其受体。 我们假设SULF 2释放PDGF和TGF-β，促进星状细胞活化、血管生成和肿瘤生长。 在具体目标1中，我们将测试SULF 2通过使ECM和星状细胞表面的HSPG变性而从储存位点释放PDGF和TGF-β的假设。 在具体目标2中，我们将检验HCC肿瘤细胞表达SULF 2增强PDGF和TGF-β活化星状细胞并刺激肿瘤生长的假设。 在具体目标3中，我们将测试SULF 1拮抗SULF 2对PDGF和TGF-β介导的星状细胞活化的作用的假设。 这些研究的成功完成将提供新的洞察肿瘤间质相互作用的作用，在肝癌的分子发病机制，并可能导致发展的合理的针对肝癌的靶向治疗策略。 公共卫生相关性：在过去的20年里，美国原发性肝癌的发病率翻了一番，主要是由于丙型肝炎病毒感染率的增加。 如果早期发现，肝癌可以通过手术或移植治疗，但由于晚期疾病没有有效的化疗治疗，否则会迅速致命。 这项研究将调查最近发现的硫酸酯酶的功能，这些酶可以促进肝癌的生长，目的是为这种毁灭性的疾病开发有效的治疗方法。

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.