Immunohistochemical Analysis Of CD133 Expression In Human Hepatocellular Carcinoma And Correlations Between Its Expression And Clinicopathological Factors

Hepatocellular carcinoma is the third common in China, the sixth common maliganancies worldwide. Its global incidence was 564,000 in 2000, 55% of which was in China. Due to its high maliganancy, high incidence of recurrence after surgeries and resistance to traditional therapies, the overall surival is still unsatisfactory.Recently, the cancer stem cells theory gave us a new insight into the tumor biological behavior. According to this theory, only a small amount of tumor cells should be responsible for the initiation, progression, metastasis and recurrence of tumors, and those cells are all characteristics of self-renewal ability and multiple differentiation potential. To date, this theory has gained supports from researches in various maliganancies, include leukemia, brain tumors, breast carcinoma, colorectal carcinoma and pancreatic carcinoma. A frequently used sorting markerin these experiments is the cell surface glucosylated protein CD133. Research on CSCs of hepatocellular carcinoma also revealed that CD133-positive cells possess a greater colony-forming efficiency, higher proliferative output, and a greater ability to form tumor in vivo, all of which indicates that CD133 is a potential surface marker of HCC CSCs. Deeper understanding of its expression in HCC may help us better understand the biological behavior of HCC and provides some insight into the future anti-tumor drug research targeted at CD133-postive cells.At presence, most research on HCC CSCs are based on HCC cell lines, the characteristics of those HCC cell lines might change because of long time culture in vitro. So, it is not known to what extent can those conclusions match the real condition in human. And its little known about its expression in human HCC tissues and its correlations with clinicopathological factors.By using immunohistochemistry, we systematically investigated the expression of CD133 in normal human liver, human cirrhotic liver, HCC and its adjacent non-tumor liver tissue, portal thrombosis, metastatic HCC in lung, xenograft of HCC cell lines in NOD/SCID mice, FAH-/--induced HCC. Also, we detected co-expression of CD133 with AFP and Ki-67 antigen, and we analyzed the correlations between CD133 expression in HCC and the major clinocopathological factors.Our results shows: 1. The expression of CD133 is significantly associated with serum AFP level, the existence of cirrhosis, tumor grade, AFP and Ki-67 expressions, higher expression of CD133 can be found in high tumor grade HCC tissues expressing AFP and Ki-67 from patients with higher serum AFP level, complicating cirrhosis; 2. There is no obvious difference between the expression of CD133 in portal thrombosis and its origin, and we didn't find the expression of CD133 in metastatic HCC in lung that we tested, which might indicates that the sustain of its growth in lung have no association with CD133; 3. We found there are universal apical staining of CD133 in bile ducts of human and mouse liver triad area, human cirrhotic liver triad area and in hyperplastic bile ducts in HCC stroma and its adjacent non-tumor liver tissues, but this pattern of its expression is different from what in HCC, indicating that different expression patterns presents different states of differentiation or function in these two types of cells; 4. In those HCC specimens expressing both CD133 and Ki-67, CD133 was highly expressed in the areas where Ki-67 was also highly expressed, but the co-expression of these two antigens showed that only a small amount of CD133-positive HCC cells expressed Ki-67 simultaneously, which indicates CD133-positive HCC cells went into cell cycle temporarily and went back to G0 soon after asymmetric cell division, and remains quiescent until next division.Our results shows, although CD133+ HCC cells have some CSCs like properties, and is correlated with clinicopathological factors, their role in tumor metastasis remains unclear, and its expression can be found in bile ductal structures universally. Our resluts gave further evidence towards the role of CD133 in the biological behavior of HCC and its relationship with the genuine hepatocarcinoma stem cells.