Abstract LB-341: CD95/FAS promotes tumorigenesis

Abstract

Abstract FAS/CD95 has been known as a typical death receptor that enhances cell apoptosis mainly in the immune system. Recent studies indicate that CD95 expression is rarely absent or down-regulated in solid tumors and CD95L, the cognate ligand that binds cell membrane CD95, is constantly shown to be elevated in patient serum as well as tumor microenviroment, raising the question whether CD95 acturally enhances tumorigenesis and through what mechanisms. By stably knocking down endogeneous CD95 expression level using lentivirus based shRNA in six different tumor cell lines that represent liver (HepG2), colon (HCT116), renal (CAKI-1), breast (MCF7), ovary (SKOV3ip1 and HeyA8), in all cases the CD95 knockdown tumor cell lines show a clear reduction in proliferation rate comparing with the corresponding vector control cells. Injection CD95 knockdown SKOV3ip1 cells i.p. into nude mice according to method of well established xenograft ovary cancer animal model again shows a reduced tumor load and this is also confirmed by using a early passage human ovary cancer cell line MONTY-1. Human neutralizing anti-CD95L mAb (NOK-1) rather than mouse anti-CD95 mAb (MFL3) injection into these xenografted nude mice significantly reduced the tumor load, indicating that it's the CD95L secreted by tumor cells rather than the mice microenviroment that stimulates the tumor proliferation. Knocking down FasL expression from the six tumor cell lines mentioned above reduced cell proliferation even more dramatically than knocking down Fas and some cell lines, like HepG2, CAKI-1, MCF7 and HeyA8, even stop growing with reduced FasL expression. The reduced tumor formation by losing FAS/CD95 was also confirmed in vivo in two animal models: DEN induced liver cancer model by using FAS/CD95 liver specific knockout mice and Ade-Cre induced ovary cancer mouse model by generating Fas knockout mice from a mice stain with background of mutated k-ras and deleted Pten expression (LSK-K-ras(G12D/+)Pten(loxP/loxP)). The tumorigenic activity of CD95 is further identified as mediated through the CD95L-CD95-JNK-c-Jun-Fos and EGR1 pathway. These results demonstrate that CD95 plays a major growth promoting role during tumorigenesis and suggest that efforts to inhibit its activity rather than to enhance its activation should be considered during cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-341.