Failure of FasL Mediated Pathways in Tumor Angiogenesis

FasL 介导的肿瘤血管生成途径失败

• 批准号: 6697127
• 负责人: VIJAY H. SHAH
• 金额: $ 21.54万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697127
• 关键词: CD95 molecule; adenomatous polyps; angiogenesis; apoptosis; athymic mouse; bone marrow transplantation; cadherins; cell cell interaction; colorectal neoplasms; extracellular matrix proteins; gene induction /repression; genetic regulatory element; laboratory mouse; metalloendopeptidases; neoplasm /cancer blood supply; neoplastic growth; preneoplastic state; proteolysis; transforming growth factors

DESCRIPTION (provided by applicant): Colorectal cancer is the second leading cause of cancer deaths in the United States but is preventable through the removal of precancerous adenomatous polyps. New vessel growth (angiogenesis) is a prerequisite for polyp growth beyond 2-3mm3 and is consequently an attractive target for cancer prevention. Endothelial cells are sensitive to killing by epithelial-derived membrane-bound Fas ligand (FasL) but are resistant to killing by cleaved FasL in vitro. Thus, in epithelial tissues that express FasL, such as precancerous colorectal polyps, cleavage of FasL may be required before angiogenesis and tumor progression can proceed. We propose that angiogenesis enabled by FasL cleavage or its loss of expression is an important checkpoint for the development of colorectal cancers. In support of this hypothesis, our preliminary data suggest that: 1) colorectal tumor angiogenesis and tumor growth are stimulated when functional FasL protein is absent; 2) FasL expressed in colorectal cancer cells is cleaved to a non-functional cleaved form by the matrix metalloproteinase, matrilysin and; 3) FasL gene expression is silenced by transforming growth factor beta (TGFbeta) signaling proteins Smad2 and Smad4. These observations provide the foundation of our CENTRAL HYPOTHESIS that inhibition of tumor angiogenesis by epithelial-derived membrane-bound FasL is controlled at the level of FasL protein cleavage or gene silencing. This hypothesis will be tested through the following specific aims: SPECIFIC AIM 1: Demonstrate that epithelial-derived FasL and cleaved FasL differentially regulate endothelial cell apoptosis and tumor growth and tumor angiogenesis in vitro and in vivo; SPECIFIC AIM 2: Demonstrate that cleavage of FasL by matrilysin is required for angiogenesis in colorectal tumors expressing FasL; and SPECIFIC AIM 3: Determine the mechanism through which TGFbeta signaling proteins negatively regulate beta-catenin/Tcf transactivation through the Tcf response element. We are optimistic that successful completion of this proposal will provide new insights into how epithelial-endothelial cells interact to modulate colorectal tumor growth and angiogenesis. In addition, these studies will provide further insight into FasL regulation at both the gene and protein level. These insights may lead to novel and effective therapeutic strategies that target this pathway to prevent angiogenesis, and thereby prevent colorectal tumor development growth and spread.

描述（由申请人提供）：结直肠癌是第二大领先 美国癌症死亡的原因，但可以通过 去除癌前腺瘤息肉。新血管生长（血管生成）是 息肉生长超过2-3mm3的先决条件，因此是一个吸引人的 预防癌症的目标。内皮细胞对杀死敏感 上皮衍生的膜结合的FAS配体（FASL），但对 在体外裂解的FASL杀死。因此，在表达的上皮组织中 FASL，例如癌前大息息肉，可能需要FASL的裂解 在血管生成和肿瘤进展之前。我们提出了这一点 通过FASL裂解或其表达丧失使血管生成是重要的 检查点的开发结直肠癌。支持这个 假设，我们的初步数据表明：1）结直肠肿瘤血管生成 当缺乏功能性FASL蛋白时，刺激肿瘤生长； 2）FASL 在结直肠癌细胞中表达 由基质金属蛋白酶，母乳蛋白和； 3）FASL基因表达 通过转化生长因子β（TGFBETA）信号传导蛋白沉默 Smad2和Smad4。这些观察为我们的中心提供了基础 假设上皮抑制肿瘤血管生成 膜结合的FASL在FASL蛋白裂解或基因的水平上受到控制 沉默。该假设将通过以下特定目的进行检验： 特定目标1：证明上皮衍生的FASL和裂解的FASL 差异调节内皮细胞凋亡和肿瘤生长和肿瘤 体外和体内血管生成；特定目的2：证明乳沟的 fasl由母脂蛋白是表达结直肠肿瘤的血管生成所必需的 fasl;和特定目标3：确定TGFBETA的机制 信号蛋白通过负调节β-catenin/tcf反式激活的蛋白质通过 TCF响应元素。我们乐观地完成了这一成功的完成 提案将为上皮细胞细胞提供新的见解 相互作用以调节结直肠肿瘤的生长和血管生成。此外， 这些研究将在这两个方面都有进一步的了解 基因和蛋白质水平。这些见解可能导致新颖有效 针对这种防止血管生成的途径的治疗策略， 从而防止结直肠肿瘤的发育生长并扩散。