Introduction Hepatocellular carcinoma HCC is commonly found

Introduction Hepatocellular carcinoma (HCC) is commonly found in Taiwan and its prognosis is unsatisfactory with surgical or non-surgical treatment modalities. Hepatic stem order Mifepristone are indefinite as cells that have the ability to perpetuate themselves through self-renewal and to differentiate into mature cells by multiple signaling pathways. Histologically, the human liver consisted of three types of liver cells: mature hepatocytes, cholangiocytes, and bipolar adult hepatic stem/progenitor cells (HPC). These three types of cell are commonly regarded as the primary targets of malignant transformation in the liver if exposed to carcinogens in vivo or in vitro. The most important and useful property of stem cells is that of self-renewal. HPC are responsible for the regeneration of hepatocytes or cholangiocytes when the liver is injured. Because of this characteristic, striking parallels can be found between stem cells and cancer cells which may regulate self-renewal. However, cancer cells may include cancer stem cells (CSC) with indefinite potential for self-renewal, that initiate tumorigenesis. The mechanisms directing the transformation of stem cells to CSC and HCC remain to be elucidated. The goal of the current studies is to apply such insight to clinical medicine and to develop a better classification system of liver cancer. The existence of CSC in solid tumors was first reported in 2003, and it was stated that such a small number of cells as CD44+CD24-/low lineage cells from human breast cancer tumors were able to initiate new tumors. More recently, highly tumorigenic cells with distinct surface marker phenotypes were indentified in tumors of the GI tract and other solid tumors. Similarly, liver cancer/progenitor cells in HCC have been identified in previous reports. In a study by Zhu et al, CD133+ cancer cells possessed stem cell properties, including higher proliferative potential, greater colony-forming efficiency, self-renewal and differentiating capacity than CD133– cells. Therefore, a set of surface molecule markers could more accurately define the cancer stem cell subpopulation responsible for the initiation and progression of HCC.
Defining features of liver progenitor cells Four possible hepatic stem cells are identified in the canal of Haering (proximal biliary tree): intralobular bile ducts, periductal “null” mononuclear cells, and peribiliary hepatocytes as shown in Fig. 1. Experimental induction of liver stem/progenitor cells in rodents has been extensively studied in liver chemical injury models and carcinogenesis. The application of a variety of experimental protocols in animal models resulted in activation and proliferation of adult liver stem/progenitor cells, often referred to as oval cells. Oval cells are putative liver stem/progenitor cells and were first described by Opie in 1944, and later by Farber in 1956. Activation and proliferation of hepatic progenitor cells have been reported in precancerous conditions, such as chronic inflammation (hepatitis B/hepatitis C, alcoholic hepatitis and steatohepatitis). Therefore, HPC could be a source of cancer stem cells in HCC.
What are the cancer stem cells? CSC within a solid tumor give rise to various differentiated tumor cells, and ultimately drive tumor growth and metastasis. The modern tools of stem cell biology have provided strong evidence to show that CSC arise from both normal stem cells and from non self-renewing progenitor cells. Importantly, the term “cancer stem cell” is an operative definition that does not necessarily have a developmental relationship to normal stem cells, but a subset of cells within a tumor can self-renew and elaborate tumor heterogeneity. Ultimately, the definition depends on the assays of self-renewal and tumorigenicity. Some aggressive tumors may have a high percentage of CSC, and chemotherapeutic treatments may increase the frequency of CSC in a tumor because of the non-stem cancer cells killed by chemo agents. In addition, sub-clones of CSC will develop into tumorigenic and non-tumorigenic progeny. These results suggest that activation of oncogenic pathways in a cellular background of genetic instability, coupled with an inherent ability to self-renew, is involved in the acquisition of metastatic behavior in the CSC population of tumors derived from pluripotent cells.