The Role of CD95 as a Tumor Promoter

CD95 作为肿瘤启动子的作用

• 批准号: 7250259
• 负责人: Marcus E. Peter
• 金额: $ 28.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250259
• 关键词: Affect; Alleles; Apoptosis; Apoptosis Promoter; Apoptotic; Biological Assay; Biological Models; Cancer Patient; Caspase; Cell model; Cell physiology; Cells; Cessation of life; Classification; Death Domain; Development; Down-Regulation; Drug resistance; Exposure to; Family member; Genes; Growth; Human; Immune; Immune system; In Vitro; Lead; Lymphocyte; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutate; Mutation; NF-kappa B; Nature; Numbers; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Point Mutation; Principal Investigator; RNA Interference; Refractory; Regulation; Reporting; Resistance; Role; Serum; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Staging; Stimulus; Surface; T-Lymphocyte; TNFRSF6 gene; Testing; Tumor Cell Line; Tumor Necrosis Factor Ligand Superfamily Member 6; Tumor Promoters; Tumor Promotion; Tumor Suppressor Proteins; Tumorigenicity; Type I Epithelial Receptor Cell; Up-Regulation; Urokinase; Variant; adenylate kinase; base; cancer therapy; caspase-8; cell motility; chemotherapy; cytotoxic; design; in vivo; insight; knock-down; mouse model; mutant; neglect; neoplastic cell; novel; programs; promoter; receptor; response; tumor; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): The death receptor CD95 (APO-I/Fas) is best known for its apoptosis inducing activity which involves recruitment of the adaptor molecule FADD and initiator caspases to the intracellular death domain of the receptor. Despite its apoptotic potential most human tumors are refractory to the cytotoxic effects of CD95 ligand. This is due either to upregulation of antiapoptotic genes, functional elimination of CD95 apoptosis signaling pathway components, mutation or downregulation of CD95. In contrast, CD95 ligand (CD95L) levels are elevated in many cancer patients and in patients receiving chemotherapy, either systemically in the serum or within the tumor itself. This has mainly been viewed as an immune escape mechanism to eliminate infiltrating lymphocytes. We recently found that CD95L induces increased motility and invasiveness in multiple apoptosis resistant tumor cells. Engagement of CD95 triggered activation of multiple signaling pathways, 3 of which - activation of NF-kappaB, Erkl/2 and caspase-8 - were found to contribute to this novel activity of CD95. We also reported that the expression of a combination of wild-type and mutant CD95, a situation frequently found in human tumors carrying a heterozygous mutation in the death domain of CD95, completely blocks apoptosis signaling but allows full activation of nonapoptotic pathways. We hypothesize that CD95 on apoptosis resistant tumor cells functions as a tumor promoting receptor and that acquiring a point mutation in one allele of CD95 converts the tumor suppressor CD95 into a tumor promotor. Furthermore we hypothesize that increased concentrations of CD95L found in cancer patients can contribute to increased tumorigenicity of tumors. To test these hypotheses in vitro and in vivo we propose the following three specific aims: Specific Aim 1: Determine the mechanism by which CD95 induces tumorigenic pathways. Specific Aim 2: Identify and characterize the CD95 induced genes that regulate CD95's tumor promoting activities. Specific Aim 3: Test whether chemotherapeutic drugs can induce invasiveness of drug resistant tumor cells. Our studies may provide the means to counteract the novel tumorigenic activities of CD95 by either blocking the activity of CD95L, the tumorigenic signaling pathways, or the tumorigenic genes activated in response to CD95 stimulation.

描述（由申请人提供）：死亡受体CD95（APO-I/Fas）以其细胞凋亡诱导活性而闻名，该活性涉及将接头分子FADD和起始半胱天冬酶募集至受体的细胞内死亡结构域。尽管具有凋亡潜力，但大多数人类肿瘤对 CD95 配体的细胞毒性作用具有抵抗力。这是由于抗凋亡基因的上调、CD95 凋亡信号通路成分的功能性消除、CD95 的突变或下调。相比之下，许多癌症患者和接受化疗的患者的 CD95 配体 (CD95L) 水平升高，无论是在血清中全身还是在肿瘤本身内。这主要被视为消除浸润淋巴细胞的免疫逃逸机制。我们最近发现 CD95L 会诱导多种抗凋亡肿瘤细胞的运动性和侵袭性增加。 CD95的参与触发了多种信号传导途径的激活，其中3种——NF-κB、Erk1/2和caspase-8的激活——被发现有助于CD95的这种新活性。我们还报道，野生型和突变型 CD95 的组合表达（一种在 CD95 死亡结构域携带杂合突变的人类肿瘤中常见的情况）完全阻断细胞凋亡信号传导，但允许非细胞凋亡途径的完全激活。我们假设抗凋亡肿瘤细胞上的 CD95 作为肿瘤促进受体发挥作用，并且在 CD95 的一个等位基因中获得点突变会将肿瘤抑制因子 CD95 转化为肿瘤促进因子。此外，我们假设癌症患者中 CD95L 浓度的增加可能会导致肿瘤的致瘤性增加。为了在体外和体内测试这些假设，我们提出以下三个具体目标： 具体目标 1：确定 CD95 诱导致瘤途径的机制。具体目标 2：鉴定并表征调节 CD95 肿瘤促进活性的 CD95 诱导基因。具体目标3：测试化疗药物是否可以诱导耐药肿瘤细胞的侵袭性。我们的研究可能提供通过阻断 CD95L 的活性、致瘤信号通路或响应 CD95 刺激而激活的致瘤基因来抵消 CD95 的新型致瘤活性的方法。