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 cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl(4)-induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [(3)H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by 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 that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.
Song
E
E
Department of Nephrology, University Hospital Essen, Germany.
Chen
J
J
Ouyang
N
N
Wang
M
M
Exton
M S
MS
Heemann
U
U
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins; D002450:Cell Communication; D003110:Colonic Neoplasms / Q000473:pathology*; D007728:Kupffer Cells / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000276:immunology / Q000473:pathology*; D008106:Liver Cirrhosis, Experimental / Q000473:pathology*; D008214:Lymphocytes; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D001426:Bacterial Proteins; C414536:FasR protein, Rhodococcus fascians; D014157:Transcription Factors