Regulation of the Tumor Microenvironment in Hepatocellular Carcinoma

肝细胞癌肿瘤微环境的调节

基本信息

批准号：
8620618
负责人：
Martin Ernesto Fernandez-Zapico
金额：
$ 31.74万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8620618
关键词：
Biochemical Cause of Death Cell Death Cell Proliferation Cell model Cellular biology Cessation of life Collaborations Data Development Diethylnitrosamine Disease Early Diagnosis Employee Strikes Erinaceidae Future GLI gene Genetic Genetically Engineered Mouse Grant Growth Growth Factor Heparan Sulfate Proteoglycan Heparin Binding Growth Factor Heparitin Sulfate Hepatocarcinogenesis In Vitro Incidence Individual Interleukin-6 Knock-out Lead Ligand Binding Ligands Liver Malignant Neoplasms Malignant neoplasm of liver Mediating Methods Molecular Mus Mutate Pathogenesis Pathway interactions Pharmaceutical Preparations Play Primary carcinoma of the liver cells Process Regulation Research Role Signal Pathway Signal Transduction Site Staging Study Section Sulfatases Tertiary Protein Structure Testing Time Transcriptional Activation Transforming Growth Factors Transgenic Mice Transgenic Organisms Variant Work base cancer therapy cancer type effective therapy extracellular glypican 3 improved in vivo mouse model novel novel therapeutic intervention overexpression polysulfated glycosaminoglycan receptor stellate cell transcription factor treatment strategy tumor tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) causes about 700,000 deaths each year, and its incidence in the US has tripled over the past 30 years. Available therapies are curative only in early-stage HCC. Better early-detection methods and treatments will require a greater understanding of the molecular mechanisms regulating the initiation and growth of HCC. We have identified a role for sulfatase 2 (SULF2), an extracellular endosulfatase, in HCC pathogenesis and are especially excited about the recent spontaneous development of liver cancers in our transgenic mice overexpressing SULF2 in the liver. Our previous work has shown that SULF2 releases heparin-binding growth factors from heparan sulfate glycosaminoglycan (HSGAG) storage sites in the extracellular compartment, increases growth factor signaling, and promotes HCC tumorigenesis. These results show that SULF2 exerts its effects in HCC in part through modulation of the Wnt signaling pathway. We have now identified the target molecule of this newly identified SULF2-Wnt signaling as the transcriptional factor GLI1, an effector of the Hedgehog pathway. Moreover, we have discovered that this newly identified SULF2-Wnt-GLI1 axis activates two major regulators of the HCC tumor microenvironment, transforming growth factor ¿ (TGF¿) and interleukin 6 (IL-6). We will use biochemical and cell biology methods, structural and functional analyses, and in vitro and in vivo approaches to systemically investigate the mechanistic role of the novel SULF2-Wnt-GLI1 axis in the HCC microenvironment and tumorigenesis. Successful completion of these studies will increase our understanding of the pathogenesis of HCC and allow future testing of rational strategies for treatment of HCC based on these findings. Overall, this proposal is potentially of high impact given the lack of effective treatments for advanced HCC. The findings from this research will also likely be generalizable to other cancer types because of the known involvement of SULF2, the Wnt pathway, and GLI1 in other tumors.

描述（由申请人提供）：肝细胞癌 (HCC) 每年导致约 70 万人死亡，其在美国的发病率在过去 30 年中增加了两倍，现有疗法仅对早期 HCC 具有疗效，并且需要更好的早期检测方法。治疗需要更多的分子机制来调节 HCC 的发生和生长。我们已经确定了硫酸酯酶 2 (SULF2)（一种细胞外酶）的作用。内硫酸酯酶在 HCC 发病机制中的作用，并且对最近在肝脏中过度表达 SULF2 的转基因小鼠中自发发展肝癌感到特别兴奋，我们之前的工作表明，SULF2 从硫酸乙酰肝素糖胺聚糖 (HSGAG) 储存位点释放肝素结合生长因子。这些结果表明，SULF2 部分通过调节 HCC 发挥其作用。 Wnt信号通路。我们现在已经鉴定出这个新鉴定的SULF2-Wnt信号传导的靶分子是转录因子GLI1，它是Hedgehog通路的效应子。此外，我们还发现这个新鉴定的SULF2-Wnt-GLI1轴激活两个主要的信号通路。 HCC 肿瘤微环境的调节因子，转化生长因子 ¿ (TGF¿) 和白细胞介素 6 (IL-6) 我们将使用生化和细胞生物学方法、结构和功能分析以及体外和体内方法来系统地研究新型 SULF2-Wnt-GLI1 轴在细胞中的机制作用。 HCC 微环境和肿瘤发生的成功完成将增加我们对 HCC 发病机制的了解，并允许未来根据这些发现测试合理的 HCC 治疗策略。鉴于晚期 HCC 缺乏有效的治疗方法，这项研究的结果也可能推广到其他癌症类型，因为已知 SULF2、Wnt 通路和 GLI1 参与其他肿瘤。