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P-Glycoprotein Expression during Tumor Progression in the Rat Liver¹

The Ontario Cancer Institute, The Princess Margaret Hospital, and the Department of Medical Biophysics [G. B., V. L.], the Faculty of Dentistry [G. B.], and the Department of Pathology [R. S., S. R.], University of Toronto, Toronto, Ontario, Canada

P-Glycoprotein (Pgp) has been shown to mediate multidrug resistance in tumor cell lines. Overexpression of Pgp has been detected in clinical cancer samples of many histological types. The basis and biological significance of such increases in Pgp expression are not well understood. In this study, the expression of Pgp during stepwise progression to rat liver cancer was examined to investigate the possible role of Pgp in carcinogenesis. An immunohistochemical technique was used to detect Pgp at the single-cell level, in a large number of liver nodules, hepatocellular carcinoma, and in distant metastases of the carcinomas. The results showed that distinct changes in Pgp expression occurred during stepwise liver carcinogenesis and that these changes were closely associated with the microscopic anatomy of the lesions. In contrast to -glutamyl transpeptidase and glutathione S-transferase-7.7, whose expression appeared to correlate with the early steps of liver carcinogenesis, Pgp expression was higher in the large hyperplastic nodules and in hepatocellular carcinomas than in the early microscopic lesions. A particularly striking finding was the consistent expression of Pgp in the lung metastases. These findings suggested that Pgp was associated with a more progressed malignant phenotype in liver carcinogenesis.

¹ This investigation was supported by Public Health Service Grants CA37130 (V. L.) and CA45361 (S. R.) from the National Institutes of Health and by the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed, at The Ontario Cancer Institute, 500 Sherbourne St., Toronto, Ontario, Canada, M4X 1K9.

Received 1/24/92. Accepted 7/20/92.

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