The Role of CD95 as a Tumor Promoter

描述(申请人提供)：死亡受体CD95(APO-I/Fas)最为人所知的是其诱导凋亡的活性，它涉及到适配器分子FADD和启动子caspase到受体的细胞内死亡区域的募集。尽管CD95具有诱导细胞凋亡的潜能，但大多数人类肿瘤对CD95配体的细胞毒作用都是耐药的。这可能是由于抗凋亡基因上调、CD95凋亡信号通路元件的功能消除、CD95基因突变或下调所致。相比之下，CD95配体(CD95L)水平在许多癌症患者和接受化疗的患者中升高，无论是在血清中还是在肿瘤本身中。这主要被认为是一种免疫逃逸机制，以消除浸润性淋巴细胞。我们最近发现，CD95L可诱导多种耐凋亡肿瘤细胞的运动能力和侵袭力增加。CD95的激活触发了多个信号通路的激活，其中3个信号通路--核因子-kappaB、Erk1/2和caspase-8的激活与CD95的这一新活性有关。我们还报道，野生型和突变型CD95的组合表达，这种情况经常在携带CD95死亡区域杂合突变的人类肿瘤中发现，完全阻断了凋亡信号，但允许完全激活非凋亡通路。我们假设抗凋亡肿瘤细胞上的CD95作为促癌受体发挥作用，并且在CD95的一个等位基因上获得点突变会将肿瘤抑制因子CD95转化为促癌因子。此外，我们假设在癌症患者中发现的CD95L浓度增加可以促进肿瘤的致瘤性增加。为了在体外和体内验证这些假说，我们提出了以下三个特定目标：特定目标1：确定CD95诱导肿瘤发生的机制。特异性目的2：鉴定调控CD95‘S促肿瘤活性的CD95诱导基因。具体目的3：检测化疗药物能否诱导耐药肿瘤细胞侵袭。我们的研究可能提供了通过阻断CD95L的活性、致瘤信号通路或CD95刺激后激活的致瘤基因来对抗CD95新的致瘤活性的方法。

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.