Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas mediated apoptosis

Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon can cer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat l ivers. Treatment with conditioned media of Kupffer cells isolated from CCl4 -induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the inc idence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kup ffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was ev aluated using [H-3]-release assay. RCN-9 cells were resistant to cytotoxici ty mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced b y TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti- FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand -induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN- 9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest t hat Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cel ls to FasR-mediated apoptosis by up-regulating the receptors, which thus pr epare them to be eliminated by infiltrating lymphocytes. (C) 2001 Cancer Re search Campaign.