Occurrence of Oval–Type Cells in Hepatitis B Virus—Associated Human Hepatocarcinogenesis

Abstract

Proliferation of a new population of epithelial cells with distinct structure, as well as cytokeratin and alpha-fetoprotein expression, was observed in nonneoplastic liver tissues from 14 cases (13 hepatitis B virus-positive) of human hepatocellular carcinoma. These cells were characterized by oval nuclei; scant, pale cytoplasm; small cell size; and cross-reaction with a monoclonal antibody against rat oval cells. These putative human oval cells were strongly positive for cytokeratin 19 and displayed considerable heterogeneity in alpha-fetoprotein and albumin expression. The oval cells were most prominent in actively regenerating nodules and in liver tissue surrounding the cancer. Oval cells and transitional types of cells appear to be the principal producers of alpha-fetoprotein in the regenerating liver. Cancer cells positive for cytokeratins 8, 18 and 19 were observed in half the hepatocellular carcinomas studied. The data suggest that a new cell population structurally similar to oval cells seen in early stages of chemical hepatocarcinogenesis in rats is consistently present in regenerating liver lesions associated with human hepatocellular carcinoma. Furthermore, it is possible that the proliferation of these oval-type cells may partly account for the elevation of serum alpha-fetoprotein frequently seen in precancerous stages of hepatitis B virus-associated human hepatocellular carcinoma.

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

“…Although not all cases of hepatocellular carcinoma with ezrin expression had CK19 expression, these results suggest that at least some cases of hepatocellular carcinoma with ezrin expression are derived from hepatic progenitor cells. The association of ezrin expression with high serum AFP, which is also a marker of progenitor cell compartments, 25 is compatible with a progenitor cell origin for these tumors. The fact that some cases of hepatocellular carcinoma with ezrin expression showed negative CK19 expression may be due to the fact that cases of hepatocellular carcinoma that are consistent with a progenitor cell origin may not necessarily have positive CK19 expression, as previously described.…”

“…The fact that some cases of hepatocellular carcinoma with ezrin expression showed negative CK19 expression may be due to the fact that cases of hepatocellular carcinoma that are consistent with a progenitor cell origin may not necessarily have positive CK19 expression, as previously described. 10 Several studies using detailed immunophenotyping, with CK19, CK7, or OV6 for example, showed that 28-50% of cases of hepatocellular carcinoma derive from progenitor cells and their progeny, 9,11,25,26 a frequency that is compatible with cases of hepatocellular carcinoma with ezrin expression. No specific marker for hepatic progenitor cell compartment has yet been described.…”

Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver

“…Novel cell types reminiscent of progenitor (stem)-like cells have been identified in human liver. 29,32,33 De Vos et al found small numbers of cells by electron microscopy that were difficult to detect by routine light microscopy. 29 Similarly, Ruck et al, 32 reported similar small numbers of oval-like cells in hepatoblastoma tumors, which they speculated might be precursors of ductular biliary cells and hepatocytes.…”

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

“…Given the association between experimental models of hepatotoxicity and carcinogenesis, it is not surprising that oval cells have been identified in acute and chronic human liver pathologies including HBV/ HCV infection, hemachromatosis and alcoholic liver disease. [32][33][34][35][36][37][38][39] …”