The Role of CD95 as a Tumor Promoter

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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.