The identification of stem cells in human liver diseases and hepatocellular carcinoma

Abstract

Liver stem cells are thought to preside in bile ducts and the canals of Hering. They extend into the liver parenchyma at a time when normal liver cell proliferation is suppressed and liver regeneration is stimulated. In the present study 69 liver biopsies and surgically excised liver tumors were studied for the presence of liver stem cells. It was found that human cirrhotic livers and hepatocellular carcinomas (HCC) frequently exhibited isolated single scattered hepatocyte stem cells within the liver parenchyma rather than in the portal tract, bile duct or the canal of Hering. These cells expressed liver stem cell markers. HCCs also contained isolated tumor cell which expressed the same stem cell markers. The markers used were GST-P, OV-6, CK-19, Oct-3/4 and FAT10. They were identified by immunofluorescent antibody staining. HGF, EGF, CK19, AIR, H19, Nanog, Oct-3/4 and FAT10 were identified by RNA-FISH. H19 is a non-coding RNA, which is expressed in most HCCs. Results: Immunohistochemistry and RNA-FISH performed on human livers identified isolated stem cells in liver parenchyma as follows: Stem cells identified by immunohistochemical markers (OV-6 and GST-P) and RNA-FISH markers (HGF, EGF, CK19 and H19) were found scattered in the liver parenchyma of cirrhotic livers and within hepatocellular carcinomas (HCCs). Precirrhotic ASH or NASH all stained negative for these stem cells. In HCCs, 13 out of 15 had stem cells located within the tumor (78%). In cirrhotic livers, 12 out of 28 (37%) had liver parenchymal stem cells present. In one case of stage 3 precirrhosis, stem cells were also found. Double staining for the markers showed colocalization of the markers in stem cells. Stem cells were found in 33% of HBV, 47% of HCV, 25% of alcoholic steatohepatitis (ASH) and 17% of non-alcoholic steatohepatitis (NASH). The frequency of stem cells found in the different disease categories correlates with the frequency of HCC occurring in these different diseases.

Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets

“…In HCCs, 13 out of 15 had stem cells located within the tumor (78%). In cirrhotic livers, 12 out of 28 (37%) had liver parenchymal stem cells present [69] .…”

FAT10 mediates the effect of TNF-α in inducing chromosomal instability

“…FAT10 was even recently implicated to be a HCC stemcell marker (Oliva et al, 2010b) as well as an epigenetic marker for liver preneoplasia in a drug-primed mouse model of tumorigenesis (Oliva et al, 2008). FAT10 was also one of the genes that was found to be overexpressed in a carcinogeninduced rat stomach cancer model (Yamashita et al, 2002).…”

Epigenetic Mechanisms in Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Potential New Link Between Stem Cells, Virology and Cancer

“…HPCs are small periportal cells capable of proliferation and differentiation into both hepatocytes and bile ductular epithelium (Clouston et al, 2005;Roskams, 2003). They express stem cell, hepatocyte and bile duct cell markers, including CD133, Nanog, α-Fetoprotein (AFP), CK19, Lin29 and c-Myc (Clouston et al, 2005;Oliva et al, 2010). Their frequency increases with the severity of the liver disease and inversely correlated with response to treatment (Oliva et al, 2010;Tsamandas et al, 2006).…”

“…They express stem cell, hepatocyte and bile duct cell markers, including CD133, Nanog, α-Fetoprotein (AFP), CK19, Lin29 and c-Myc (Clouston et al, 2005;Oliva et al, 2010). Their frequency increases with the severity of the liver disease and inversely correlated with response to treatment (Oliva et al, 2010;Tsamandas et al, 2006). Further, there is evidence that HCV infection directly induces HPCs and the presence of HPCs facilitates HCV replication.…”