Dysregulation of the Tumor Microenvironment in Hepatocellular Carcinoma

肝细胞癌中肿瘤微环境的失调

• 批准号: 7918194
• 负责人: LEWIS R ROBERTS
• 金额: $ 19.95万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-19 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918194
• 关键词: Binding; Binding Proteins; Cancer Etiology; Cell Line; Cell Surface Receptors; Cell membrane; Cell surface; Cells; Cessation of life; Chronic; Cirrhosis; Coculture Techniques; Complex; Development; Disease; Endothelial Cells; Enzymes; Epithelial; Epithelial Cells; Excision; Extracellular Matrix; Feedback; Fibroblast Growth Factor; Glucosamine; Goals; Growth; Growth Factor; Heparan Sulfate Proteoglycan; Heparin; Heparin Binding Growth Factor; Heparitin Sulfate; Hepatic Stellate Cell; Hepatitis C; Human; In Vitro; Inflammation; Inorganic Sulfates; Lead; Liver; Liver Cirrhosis; Liver neoplasms; Malignant Epithelial Cell; Malignant neoplasm of liver; Mediating; Molecular; Neoplasm Metastasis; Nude Mice; Oncogenic; Operative Surgical Procedures; Pathogenesis; Pericytes; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Polysaccharides; Positioning Attribute; Primary carcinoma of the liver cells; Recurrence; Resected; Risk Factors; Role; Signal Transduction; Site; Stromal Cells; Stromal Change; Stromal Neoplasm; Sulfatases; System; TGF beta type III receptor; TGFBR3 gene; Testing; Transforming Growth Factors; Transplantation; Tumor Expansion; Tumor Suppressor Proteins; Unspecified or Sulfate Ion Sulfates; Vascular Endothelial Growth Factors; Xenograft procedure; advanced disease; angiogenesis; carcinogenesis; cell growth; chemotherapy; cytokine; effective therapy; extracellular; in vivo; insight; neoplastic cell; novel; outcome forecast; polysulfated glycosaminoglycan; public health relevance; receptor; receptor binding; response; stellate cell; sulfation; therapeutic target; tumor; tumor growth

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.

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发生和发展的基质变化很重要，但尚未完全了解。慢性炎症导致肝硬化是HCC发生的最重要的危险因素，因此间质微环境的改变在HCC的发生和进展中一定是重要的。肝硬化的特征是星状细胞/周细胞的激活和增殖，以及随之而来的细胞外基质（ECM）的扩张。星状细胞的激活依赖于血小板衍生生长因子（PDGF），一种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- (TGF-)储存在与潜在TGF-结合蛋白结合的ECM中，并通过硫酸肝素蛋白多糖（HSPG）辅助受体TGF- R3呈现给TGF- R2激活受体。作为对PDGF的反应，周细胞产生FGF、HGF和VEGF，它们依次作用于肿瘤细胞和内皮细胞，形成驱动癌变的正反馈循环。我们已经证明，最近发现的肝素降解磺化内酯酶sulg2与人类HCC的肿瘤复发和预后不良有关，并促进裸鼠肝癌异种移植的生长；相反，相关的磺化酶SULF1具有肿瘤抑制作用。巯基二硫由肿瘤细胞分泌到ECM中，在葡萄糖胺的6-O位置使hspg脱硫。6-O硫酸化是肝素结合生长因子与HSPGs结合所必需的。通过脱硫HSPGs，硫酸降低了HSPGs与生长因子的结合，将其从细胞表面和ECM中释放出来，并使其能够与受体结合。我们假设巯基磺酸释放PDGF和TGF-¿，促进星状细胞活化、血管生成和肿瘤生长。在具体目标1中，我们将检验假设，即硫酸通过在ECM和星状细胞表面脱硫HSPGs，从储存位点释放PDGF和TGF-¿。在Specific Aim 2中，我们将验证HCC肿瘤细胞表达巯基二甲砜增强PDGF和TGF-¿活化星状细胞，刺激肿瘤生长的假设。在Specific Aim 3中，我们将验证SULF1拮抗SULF2对PDGF-和TGF-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为肿瘤-基质相互作用在HCC分子发病机制中的作用提供新的见解，并可能导致针对HCC的合理靶向治疗策略的发展。公共卫生相关性：在过去20年中，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。如果发现得早，肝癌可以通过手术或移植来治疗，但由于没有对晚期疾病有效的化疗方法，否则会迅速致命。这项研究将调查最近发现的促进肝癌生长的磺胺酶的功能，目的是为这种毁灭性疾病开发有效的治疗方法。