Heterogeneity of the "oval-cell" response in the hamster liver during cholangiocarcinogenesis following Clonorchis sinensis infection and dimethylnitrosamine treatment.

BACKGROUND

Small intraportal "oval" cells which appear in the livers of humans and experimental animals after liver injury, are suspected to be early progenitor cells for both hepatocytes and bile duct cells, as well as cells of origin of hepatocellular and cholangiocellular carcinomas.

METHODS

The origin and fate of small "oval" cells expressing different immunohistologic phenotypes and ultrastructural appearance were examined in livers of Syrian hamsters during cholangiocarcinogenesis induced by dimethylnitrosamine and promoted by Clonorchis sinensis infection.

RESULTS

Three different "oval" cell types are identified in portal and/or periportal areas: 1) Small periductal cells with abundant heterochromatin and scant cytoplasm that are negative for AFP, CK19, OV-6 and GST-p (primitive oval cells); 2) Glycogen-rich cells, positive for AFP, but negative for CK19, OV-6 and GST-p mainly adjacent to ductal plates (hepatocyte-like oval cells); and 3) small cells with desmosomes and basement membrane, containing GST-p CK19 and OV-6 but negative for AFP, present in ducts (ductular-like oval cells). It appears that C. sinensis infection stimulates proliferation and differentiation of small ductular or periductal cells (primitive oval cells) into either hepatocyte-like oval cells, which mature into hepatocytes without malignant transformation, or into ductular-like oval cells.

CONCLUSIONS

We propose that the ductular-like oval cells are precursors of dysplastic ductular cells that give rise to cholangiocarcinomas after dimethylnitrosamine treatment and conclude that primitive oval cells are bipolar progenitor cells for hepatocytes and biliary cells, and that activation (initiation) of these cells by carcinogen (dimethylnitrosamine), followed by stimulation of proliferation of biliary cells by C. sinensis, promotes primitive oval cells or their progeny (ductular-like oval cells) to transform into cholangiocarcinomas.