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

Abstract

Summary 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.

Kupffer cells promote lead nitrate-induced hepatocyte apoptosis via oxidative stress

“…These data are in agreement with those indicating that the intensity of oxidative stress exhibited by post-ischaemic lobes is closely linked to Kupffer cell activity [32]. Moreover, the same trend is observed when rats are previously fed with 2 mM BSO for 2 or 3 weeks.…”

“…Cells deprived of GSH are much more prone to undergo oxidative stress since their redox balance is altered and, therefore, their ability to get rid of reactive oxygen species originated from cellular metabolism is compromised [34]. Thus, an oxidative mechanism may be a point of convergence of many different apoptogenic stimuli (i.e., H 2 O 2 , tumour necrosis factor, cycloheximide and natural killer cells, all eliciting oxidative stress) into a main signalling pathway [16,32,33,35]. It is well known that NO mediates Kupffer cell-induced reduction of mitochondrial energization in syngenic hepatoma cells [20].…”

Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice

“…5 The activation of Kupffer cells in cirrhosis may also inhibit the formation of hepatic metastases. 7 Based on previous studies, the fate of metastatic cells in the liver is determined by the expression of hepatic microvasculature adhesion molecules and the release of endothelial-derived nitric oxide (NO). Specifically, the expression of inducible vascular adhesion molecules can cause tumor cell arrest in terminal portal vein (TPV) and increase metastasis.…”

Soluble Fas ligand released by colon adenocarcinoma cells induces host lymphocyte apoptosis: an active mode of immune evasion in colon cancer

“…Although our previous study has shown that colon cancer cells may be sensitized to FasR-mediated apoptosis upon exposure to cirrhotic Kupffer cells (Song et al, 2001), under normal circumstances, they lack FasR expression, and thus may avoid suicide induced by their own soluble Fas ligand.…”