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+), in macrophages (ED-1+) and in MFs (α-smooth-muscle-actin, α-SMA+) 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.
Highlights
Cholangiocarcinoma (CC) is a primary hepatic malignancy originating from cholangiocytes of the biliary tree and possibly from cholangiocyte progenitor cells.[1,2,3,4]
Besides regulating the hemopoietic stem cell proliferation, Stem cell factor (SCF) has been implicated in inflammatory diseases, tissue remodeling––including fibrosis––and in liver regeneration after liver injury, suggesting that it may serve as a protective factor in tissues that could be susceptible to environmental–toxic injury.[14,15,16,17,18]
Further studies indicate that, in addition to its physiological functions, SCF plays a critical role in carcinogenesis and is co-expressed with its receptor, c-Kit, in various tumors, implying the possible presence of an autocrine and/or a paracrine loop.[19,20,21,22,23]
Summary
Cholangiocarcinoma (CC) is a primary hepatic malignancy originating from cholangiocytes of the biliary tree and possibly from cholangiocyte progenitor cells.[1,2,3,4] It is the second most common primary hepatic neoplasia, and its incidence has increased within the last three decades. Stem cell factor (SCF), the ligand of the c-Kit receptor, constitutes an important signal transduction system with proliferative and anti-apoptotic functions It has predominantly been depicted as a hematopoietic factor that induces stem cell maturation and differentiation.[12,13] Besides regulating the hemopoietic stem cell proliferation, SCF has been implicated in inflammatory diseases, tissue remodeling––including fibrosis––and in liver regeneration after liver injury, suggesting that it may serve as a protective factor in tissues that could be susceptible to environmental–toxic injury.[14,15,16,17,18] further studies indicate that, in addition to its physiological functions, SCF plays a critical role in carcinogenesis and is co-expressed with its receptor, c-Kit, in various tumors, implying the possible presence of an autocrine and/or a paracrine loop.[19,20,21,22,23] In this manner, it seems that several cell populations can express and quickly release SCF upon cellular assault or inflammation.[18]. Liver tumors were quantified along the surface, and grossly apparent tumors were carefully dissected from the surrounding liver tissue
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
