Expression of stem cell factor and its receptor c-Kit during the development of intrahepatic cholangiocarcinoma

Abstract

Stem cell factor (SCF) and its receptor, c-Kit, constitute an important signal transduction system with proliferative and anti-apoptotic functions. Besides regulating hemopoietic stem cell proliferation and liver regeneration, it has been implicated in the regulation of human malignancies. However, the cellular expression of the SCF-c-Kit gene system in the liver during cholangiocarcinogenesis has not been studied to date. The protein-and mRNA-expression levels of SCF and c-Kit genes were examined in normal rat liver, in isolated normal rat liver cells and in a thioacetamide-induced rat model of intrahepatic cholangiocarcinoma (CC). Immunohistochemical analysis of the normal liver showed that SCF is expressed in the wall of the hepatic artery and in some cells, which were located along the sinusoids, although it was absent from hepatocytes and biliary epithelial cells. The mRNA analysis of isolated normal liver cell populations revealed a co-expression of SCF-and c-Kit-mRNA in sinusoidal endothelial cells and in Kupffer cells, whereas passaged and cultured liver myofibroblasts (MFs) expressed only SCF. Low levels of the SCF-and c-Kit-mRNA expression could be detected in isolated hepatocytes of the normal liver. Immunohistochemical analysis of the CC tissue showed SCF positivity in proliferating biliary cells (CK-19 þ ), in macrophages (ED-1 þ ) and in MFs (a-smooth-muscle-actin, a-SMA þ ) of the tumoral microenvironment. c-Kit-positivity could be detected on hepatocytes of the regenerating nodules and on the proliferating bile ducts of CC. Compared with the normal liver tissue, SCF-mRNA from the CC tissue was upregulated up to 20-fold, whereas c-Kit-mRNA was upregulated up to fivefold. These data indicate that several cell populations may become able to express SCF and/or c-Kit during cholangiocarcinogenesis. Therefore, the SCF-c-Kit system may contribute to tumor development, for instance, by inducing proliferation of hepatocytes and of biliary cells and by acting as a surviving factor for CC cells.

Characterization of the erythropoietin/erythropoietin receptor axis in a rat model of liver damage and cholangiocarcinoma development

“…Finally, referring to previous reports from our group (Mansuroglu et al 2009) and others (Kamenz et al 2006) showing an aberrant expression of the SCF/-c-kit pathway in the same experimental model, a synergistic effect of SCF and EPO on cell functions was hypothesized. In particular, the cell populations that express the highest levels of c-kit receptor, hepatocytes of the cirrhotic nodules and hyper-proliferative CK19-positive cells, were found to be the same cell types that contribute to the greatest extent to EPO production.…”

“…In detail, the chronic administration of TAA in drinking water has been shown to induce hepatic injury with periportal fibrosis that evolves to cirrhosis and endstage neoplastic transformation of the hyper-proliferative bile ducts within the stromal tissue of the portal spaces (Mansuroglu et al 2009). …”

“…We investigated also the effects of SCF (c-kit ligand), a growth factor that we described in the same experimental model (Mansuroglu et al 2009) and that was previously identified in the same cell lines (Kamenz et al 2006). We analyzed the human CC cell line Mz-Cha-2 and found no significant changes of EpoR or EpoR-s gene expression after stimulation with the growth factors EPO and SCF, alone or in combination (Fig.…”

Recent advances in cancer stem cell research for cholangiocarcinoma

“…In young rats subjected to bile duct ligation, SCF/c-kit expression was increased in proliferating bile epithelial cells [43]. In a thioacetamideinduced rat intrahepatic cholangiocarcinoma model, SCF was expressed in the proliferating biliary cells, macrophages, and myofibroblasts of the tumor microenvironment [44]. These results indicate that SCF and c-kit are important during the process of cholangiocarcinogenesis.…”

The stem cell factor (SCF)/c-KIT signalling in testis and prostate cancer

“…The SCF gene encodes a 45 kDa glycoprotein predominantly located at plasma membrane (Mansuroglu et al 2009). The SCF protein contains three distinct regions ( Fig.…”