The role of hepatic stellate cells in the development and progression of liver cirrhosis and hepatocellular carcinoma
The behavior of tumor tissue is largely dependent on the microenvironment which, surrounding the tumor cells, is capable to inhibit or support the growth, and invasion of cancer. Besides providing a structural framework, the components of extracellular matrix can store signaling molecules in the environment or present them to cell surface receptors. This establishes a permanent crosstalk between the cellular components of the tumor. Our research activity aims to uncover these events on several levels.
We want to focus on the role of proteoglycans with particular interest of decorin, and syndecan1. The former is known to bind and inhibit TGFB1 and interferes with signal transduction. The latter is capable to bind and present growth factors and cytokines toward the surface of tumor cells. The matricellular protein thrombospondin-1 seems to be a key player in the tumor-stroma interaction. It can activate TGFB1 and with its EGF repeat domain it is capable to facilitate the activation of EGF receptor, opposing the effect of decorin. TFPI2 a serine protease inhibitor is emerging as a tumor suppressor acting against the invasion of cancer cells.
The implication of these molecules are studied not only on human tumors on expression level, but we can utilize transgenic animals, and work with cell cultures where the particular molecules are overexpressed or down regulated. The most studied model is the hepatocellular carcinoma, where surgically removed materials, animal hepatocarcinogenesis models, and in vitro hepatocarcinoma cell lines are available. To study the effect of stromal cells hepatic stellate cell are cocultured with the tumor cells. The 1st Institute of Pathology possess animal facility with permission for working with genetically engineered animals, tissue culture core facility, our laboratory is equipped with pyrosequenator, Sanger sequenator, real-time thermocycler, regular thermocyclers, equipment needed for bacterial and cellular transfections, RNA integrity measurement, fotometers. Gel documentation systems in UV and near-infrared are also available.
Prof. Ilona Kovalszky, leader of the molecular pathology laboratory
