P-Glycoprotein Expression during Tumor Progression in the Rat Liver1

P-Glycoprotein (Pgp) has been shown to mediate multidrug resis tance in tumor cell lines. Overexpression of Pgp has been detected in clinical cancer samples of many histolÃ3gica!types. The basis and bio logical significance of such increases in Pgp expression are not well understood. In this study, the expression of Pgp during stepwise pro gression 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 métastasesof 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 •¿ Y-glutamyl transpeptidase and glutathione .S-transferase-7.7, whose ex pression appeared to correlate with the early steps of liver carcinogen esis, Pgp expression was higher in the large hyperplastic nodules and in hepatocellular carcinomas than in the early microscopic lesions. A par ticularly striking finding was the consistent expression of Pgp in the lung métastases. These findings suggested that Pgp was associated with a more progressed malignant phenotype in liver carcinogenesis.