The Relationship Between Hepatic Progenitor Cells Activation And Tumor Angiogenesis In Combined Hepatocellular Cholangiocarcinoma

The relationship between hepatic progenitor cells activation and tumor angiogenesis in Combined Hepatocellular CholangiocarcinomaBackground:Hepatic progenitor cells (HPCs), which reside in canals of Hering, can be activated during the process of many kinds of chronic liver disease due to hepatic stellate cells, TNF-a, IL-6 and IFN-y. When activated HPCs can give rise to ductular reactions (DRs) and have been strongly linked to hepatic carcinogenesis. HPCs can differentiate into hepatocyte and cholangiocyte. Disorders occuring in the process can lead to different types of primary liver cancer. Combined hepatocellular-cholangiocarcinoma (CHC) is a malignant primary liver cancer that contains elements of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It accounts for about 1.0-14.2% in primary liver cancer. Despite its low incidence rate, CHC presents stronger invasiveness, worse prognosis and potential HPCs origin. Our previous research found that non-tumor Proliferative index of reactive ductular(PIDR) and Hepatic progenitor cells(HPC) activation have significant correlation in CHC. PIDR also correlates with prognosis of CHC. The underlying mechanism remains unclear. Primary liver cancer is one of the most vascularized solid tumors, in which angiogenesis plays an important role in its development, progression, and metastasis. There are many kinds of activator of angiogenesis in the blood circulation. Such as vascular endothelial growth factor(VEGF). VEGF expression is regulated by ras and correlates with tumor angiogenesis. Many kinds of tumor cells can secrete VEGF. Weidner use Microvessel density(MVD) to quantitatively evaluate the angiogenesis of tumor in early 1990s. Microvessel density is the independent risk factor for survival and recurrence of hepatocellular carcinoma. In this research, we aim to explore the correlation of hepatic progenitor activation and tumor angiogenesis in Combined Hepatocellular Cholangiocarcinoma, as well as the underlying mechanism.Methods:We retrospectively recruited 99 patients who were diagnosed with liver cancer of CHC pathologically. Clinical and prognosis data of all patients were collected too. Expression of CK7, Bmi-1, AFP, EpCAM, MVD, VEGF and PIDR were estimated by immunohistochemical technology. Using statistical analysis for the correlation between these data and their effect on prognosis of CHC.Results:1.Univariable and multivariate analysis show that MVD and PIDR≥50% are independent risk factors for survival and recurrence.2. Multiple tumor and Bmi-1 positive are independent risk factors for disease free survival.3.Tumor size>5cm and EpCAM positive are independent risk factors for overall survival.4. Cirrhosis, PIDR and EpCAM expression correlate with tumor MVD. PIDR and VEGF expression are closely related.5. Cirrhosis, nontumor VEGF,Bmi-land EpCAM expression correlate with PIDR.Conclusion:Prognosis of CHC correlates with PIDR and marks of Hepatic progenitor cells. Tumor MVD could affect disease free survival and overall survival of CHC. PIDR and EpCAM expression may affect angiogenesis of CHC probably via the up-regulation of VEGF.