Regulation of the Tumor Microenvironment in Hepatocellular Carcinoma

肝细胞癌肿瘤微环境的调节

• 批准号: 8795285
• 负责人: Martin Ernesto Fernandez-Zapico
• 金额: $ 9.33万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8795285
• 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

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（由适用提供）：肝细胞癌（HCC）每年造成约700,000人死亡，在过去的30年中，美国事件在美国发生了两倍。可用的疗法仅在早期HCC中治愈。更好的早期检测方法和治疗方法将需要更深入地了解衡量HCC倡议和生长的分子机制。我们已经确定了硫酶2（Sulf2）（Sulf2）（一种细胞外内硫糖酶）在HCC发病机理中的作用，并且对我们过度表达肝脏硫磺的转基因小鼠的肝癌最近的赞助发展特别激动。我们以前的工作表明，Sulf2从硫酸乙酰肝素糖胺聚糖（HSGAG）储存位点释放出肝素结合生长因子，可在细胞外室中储存位点，增加生长因子信号传导，并促进HCC肿瘤造影。这些结果表明，Sulf2通过调节WNT信号通路会在HCC中发挥作用。现在，我们已经确定了该新鉴定的Sulf2-Wnt信号传导的目标分子是转录因子GLI1，这是刺猬途径的效应子。此外，我们发现这种新鉴定的Sulf2-Wnt-GLI1轴激活了HCC肿瘤微环境的两个主要调节剂，转化了生长因子（TGFFO）和interleukin 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型Sulf2-Wnt-GLI1轴在HCC微环境和肿瘤发生中的机械作用。这些研究的成功完成将提高我们对HCC发病机理的理解，并根据这些发现，将来允许对HCC治疗的理性策略进行未来测试。总体而言，鉴于缺乏对高级HCC的有效治疗方法，该建议可能会产生很大的影响。这项研究的发现也可能是其他癌症类型的推广，因为Sulf2，Wnt途径和GLI1在其他肿瘤中的已知参与。