Regulation of the Tumor Microenvironment in Hepatocellular Carcinoma

描述(由申请人提供)：肝细胞癌每年导致约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肝细胞癌有效。更好的早期检测方法和治疗方法将需要更多地了解调控肝细胞癌发生和生长的分子机制。我们已经确定了硫酸酯酶2(SULF2)在肝癌发病机制中的作用，尤其令人兴奋的是，最近在我们的转基因小鼠中过度表达SULF2的转基因小鼠发生了肝癌。我们以前的工作表明，SULF2从细胞外室的硫酸乙酰肝素糖胺聚糖(HSGAG)存储位置释放肝素结合生长因子，增加生长因子信号转导，促进肝癌的发生。这些结果表明，SULF2在肝细胞癌中的作用部分是通过调节Wnt信号通路来实现的。我们现在已经确定了这个新发现的SULF2-Wnt信号的靶分子是转录因子GLI1，它是Hedgehog途径的效应因子。此外，我们还发现，这个新发现的SULF2-WNT-GLI1轴激活了肝细胞癌肿瘤微环境的两个主要调节因子-转化生长因子(TGF)和白介素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，系统地研究新的SULF2-WNT-GLI1轴在肝癌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肝癌发病机制的了解，并使未来能够根据这些发现测试合理的肝癌治疗策略。总体而言，鉴于缺乏对晚期肝癌的有效治疗，这项提议可能会产生很大的影响。这项研究的发现也可能推广到其他癌症类型，因为已知SULF2、Wnt途径和GLI1参与了其他肿瘤。

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.