The Role of CD95 as a Tumor Promoter

描述（由申请人提供）：死亡受体CD95 （APO-I/Fas）以其诱导凋亡的活性而闻名，其诱导活性涉及到受体细胞内死亡结构域的接合分子FADD和引发剂半胱天冬酶的募集。尽管CD95配体具有凋亡潜能，但大多数人类肿瘤对CD95配体的细胞毒性作用是不耐受的。这可能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突变或下调所致。相反，CD95配体（CD95L）水平在许多癌症患者和接受化疗的患者中升高，无论是在全身血清中还是在肿瘤本身中。这主要被认为是一种消除浸润淋巴细胞的免疫逃逸机制。我们最近发现CD95L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通路的激活，其中3种- NF-kappaB， Erkl/2和caspase-8的激活被发现有助于CD95的这种新活性。我们还报道了野生型和突变型CD95的结合表达，这种情况在CD95死亡结构域携带杂合突变的人类肿瘤中经常发现，完全阻断凋亡信号传导，但允许完全激活非凋亡途径。我们假设抗凋亡肿瘤细胞上的CD95作为肿瘤促进受体起作用，并且在CD95的一个等位基因中获得点突变将肿瘤抑制因子CD95转化为肿瘤启动子。此外，我们假设在癌症患者中发现的CD95L浓度的增加可能有助于肿瘤的致瘤性增加。为了在体外和体内验证这些假设，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。特异性目标2：鉴定和表征调节CD95促肿瘤活性的CD95诱导基因。特异性目的3：检测化疗药物能否诱导耐药肿瘤细胞的侵袭性。我们的研究可能通过阻断CD95L的活性、致瘤信号通路或在CD95刺激下激活的致瘤基因来抵消CD95的新致瘤活性。

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.