Regulation of the Tumor Microenvironment in Hepatocellular Carcinoma

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。 现有的治疗方法仅对早期HCC有效。 更好的早期检测方法和治疗将需要更好地了解调控HCC发生和生长的分子机制。 我们已经确定了硫酸酯酶2（SULF 2），细胞外endosulfatase，在HCC发病机制中的作用，并特别兴奋的是最近自发发展的肝癌在我们的转基因小鼠在肝脏中过表达SULF 2。 我们以前的工作表明，SULF 2释放肝素结合生长因子从硫酸乙酰肝素糖胺聚糖（HSGAG）的存储网站在细胞外室，增加生长因子信号，并促进肝癌的肿瘤发生。 这些结果表明，SULF 2在HCC中部分通过调节Wnt信号通路发挥其作用。 我们现在已经确定了这个新发现的SULF 2-Wnt信号转导的靶分子为转录因子GLI 1，Hedgehog途径的效应子。 此外，我们发现，这种新发现的SULF 2-Wnt-GLI 1轴激活了HCC肿瘤微环境的两个主要调节因子，转化生长因子（TGF）和白细胞介素6（IL-6）。 我们将使用生物化学和细胞生物学方法，结构和功能分析，以及体外和体内方法来系统地研究新的SULF 2-Wnt-GLI 1轴在HCC微环境和肿瘤发生中的机制作用。 这些研究的成功完成将增加我们对HCC发病机制的理解，并允许基于这些发现对HCC治疗的合理策略进行未来测试。 总的来说，鉴于缺乏有效的晚期HCC治疗方法，该提案可能具有很高的影响力。 这项研究的结果也可能推广到其他癌症类型，因为已知SULF 2，Wnt通路和GLI 1参与其他肿瘤。

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.