Hepatic progenitor cells in human liver tumor development

In recent years, the results of several studies suggest that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types. The available data indeed strongly suggest that most combined hepatocellular-cholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages. Hepatic progenitor cells could also be the basis for some hepatocellular carcinomas and hepatocellular adenomas, although it is very difficult to determine the origin of an individual hepatocellular carcinoma. There is currently not enough data to make statements regarding a hepatic progenitor cell origin of cholangiocarcinoma. The presence of hepatic progenitor cell markers and the presence and extent of the cholangiocellular component are factors that are related to the prognosis of hepatocellular carcinomas and combined hepatocellular- cholangiocarcinomas, respectively.

Everolimus halts hepatic cystogenesis in a rodent model of polycystic-liver-disease

AIM To develop a MRI-based method for accurate determination of liver volume(LV) and to explore the effect of long-term everolimus(EVR) treatment on LV in PCK rats with hepatomegaly. METHODS Thirty-one female PCK rats(model for polycystic-liverdisease: PCLD) were randomized into 3 groups and treatment was started at 16 wk, at the moment of extensive hepatomegaly(comparable to what is done in the human disease). Animals received: controls(n = 14), lanreotide(LAN: 3 mg/kg per 2 wk)(n = 10) or everolimus(EVR: 1 mg/kg per day)(n = 7). LV was measured at week 16, 24, 28. At week 28, all rats were sacrificed and liver tissue was harvested. Fibrosis was evaluated using quantitative image analysis. In addition, gene(quantitative RT-PCR) and protein expression(by Western blot) of the PI3K/Ak T/m TOR signaling pathway was investigated. RESULTS LV determination by MRI correlated excellent with the ex vivo measurements(r = 0.99, P < 0.001). The relative changes in LV at the end of treatment were:(controls) +31.8%;(LAN) +5.1% and(EVR) +8.8%, indicating a significantly halt of LV progression compared with controls(respectively, P = 0.01 and P = 0.04). Furthermore, EVR significantly reduced the amount of liver fibrosis(P = 0.004) thus might also prevent the development of portal hypertension. There was no difference in phosphorylation of Akt(Threonine 308) between LAN-treated PCK rats control PCK rats, whereas S6 was significantly more phosphorylated in the LAN group. Phosphorylation of Akt was not different between controls and EVR treated rats, however, for S6 there was significantly less phosphorylation in the EVR treated rats. Thus, both drugs interact with the PI3K/Ak T/m TOR signaling cascade but acting at different molecular levels.CONCLUSION Everolimus halts cyst growth comparable to lanreotide and reduces the development of fibrosis. m TORinhibition should be further explored in PCLD patients especially those that need immunosuppression.