CD44, CD133and TF Are Associated With Formation Of Portal Vein Tumor Thrombus And Poor Prognosis In Hepatocellular Carcinoma

Objectives:Hepatocellular carcinoma (hepatocellular, carcinoma, HCC) is one of the highestmalignant tumours because of early metastasization and strong invasiveness. HCC is thefifth common maliganancies worldwide. Recent statistics show that in2008there are748,300cases of HCC worldwide emerging and there are695,900cases of patients died ofHCC. The5-year survival rate of HCC is less than30%and the most important factoraffecting the survival rate of liver cancer is the metastasis and recurrence of HCC. Theformation of portal vein tumor thrombus (PVTT) is a major feature of HCC, and portal veintumor thrombus is the most important factor leading to the metastasis and recurrence ofHCC. Therefore, to improve the therapeutic effect of HCC, it is very important to researchthe risk factors leading to the formation of portal vein tumor thrombus.Rencently, the cancer stem cells (CSCs) theory gave us a novel insight into the tumorbiological behavior. According to this theory, only a small amount of tumor cells should beresponsible for the initiation, progression,metasis and recurrence of tumors, and those cellsare all characteristics of self-renewal ability and multiple differentiation potential. Studieshave shown that HCC cancer stem cells is a major cause of HCC invasion and metastasisand lead to relapse. Researcher has identified a number of HCC cancer stem cell markers,such as CD44, CD90, CD133, OV-6, ABCG2and EpCAM, of which CD44, CD133is amore common HCC cancer stem cell markers.Tissue factor (TF) is a47-kDa transmembrane glycoprotein which is the main startupfactor of physiological coagulation. Studies have shown that, beside addition toparticipation in the clotting mechanism, its function is also involved in intracellular signaltransduction, angiogenesis and tumor invasion and metastasis process. In breast cancer, colon cancer, malignant melanoma，pancreatic cancer and other types of tumors, TFincreased expression can promote tumor invasion and metastasis. Recent studies have foundthat, TF play an important role in the formation of cancer stem cells microenvironment. Bydirect or indirect methords, TF could promote procoagulant pathway and signaltransduction, stimulate tumor cells release large amounts of growth promoting factors,create favorable microenvironment of tumor stem cells, thus promoting tumor metastasisand recurrence.Based on the observations, we hypothesized weather TF promote vascular invasionand blood transfer of cancer stem cells by altering the tumor microenvironment. Thus andportal vein tumor thrombus formation related and affect clinical outcomes of HCC.Through literature review, we had not found the report about the relationship between TFand HCC cancer stem cells. Therefore, we detected the expression of CD44,CD133and TFin HCC expression CD44, CD133and TF by using immunohistochemistry in387HCCpatients.We further evaluated the relationship between the expression and clinicalpathology and prognosis of HCC.Methods:1. A total of387HCC patients (339male and48female) underwent surgical resectionbetween November2005and November2008,at the Department of Hepatobiliary SurgeryInstitute, Southwest Hospital were included. The expression of CD44,CD133and TF wasdetected by using immunohistochemistry in387HCC patients.We further evaluated therelationship between the expression and clinical pathology.2. Overall survival was calculated from the date of surgery until the date of lastcontact.and prognosis of HCC. We further evaluated the relationship between theexpression of CD44,CD133and TF and overall survival by using Kaplan-Meier and Coxmodels.Results:1.The positive expression rates of CD44, CD133and TF in HCC patients were60.47%,55.81%, and65.12%, respectively. The positive rate of co-expression of CD44and CD133(CD44+CD133+) was41.60%. The positive rate of co-expression of CD44, CD133and TF(CD44+CD133+TF+) was35.14%..The expression of CD44, CD133and TF in the portalvein tumor thrombus group was higher than no ortal vein tumor thrombus group. 2.Clinical analysis showed that individual expression of CD44, CD133or TF wasassociated with portal vein tumor thrombus, TNM staging and grading of Edmendson.CD44+CD133+and CD44+CD133+TF+had the same results (P<0.01and P<0.01,respectively).3.TF, CD44and CD133protein expression was positively correlated by usingSpearman-rank correlation analysis.(P<0.01).4. The total survival time of CD44, CD133and TF positive groups was shorter thanthe negative groups and the differences were statistically significant (P<0.01all). The totalsurvival time of CD44+CD133+group was shorter than that of non-CD44+group (P<0.01).The total survival time of CD44+CD133+TF+group was shorter than that of non-CD44+CD133+TF+group and the differences were statistically significant (P<0.01).5. Multivariate analysis suggested that portal vein tumor thrombus, TF+, CD44+CD133+and CD44+CD133+TF+were the independent risk factors of the prognosis ofHCC (P<0.01all).Conclusions:The expression of CD44, CD133and TF in the portal vein tumor thrombus group washigher than no ortal vein tumor thrombus group. TF, CD44and CD133protein expressionwas positively correlated by using Spearman-rank correlation analysis. The total survivaltime of CD44, CD133and TF positive groups was shorter than the negative groups and thedifferences were statistically significant (P<0.01all). The total survival time of CD44+CD133+group was shorter than that of non-CD44+CD133+group (P<0.01). The totalsurvival time of CD44+CD133+TF+group was shorter than that of non-CD44+CD133+TF+group and the differences were statistically significant (P<0.01). Multivariate analysissuggested that portal vein tumor thrombus, TF+, CD44+CD133+and CD44+CD133+TF+were the independent risk factors of the prognosis of HCC. The positive expression ofCD44, CD133and TF were associated with each other and closely correlated with theinformation of portal vein tumor thrombus，which may indicate the poor prognosis ofHCC．...