REDUCTION IN THE EXPRESSION OF GLUCOSE-TRANSPORTER PROTEIN GLUT-2 IN PRENEOPLASTIC AND NEOPLASTIC HEPATIC-LESIONS AND REEXPRESSION OF GLUT-1 IN LATE STAGES OF HEPATOCARCINOGENESIS

Expression of two important glucose transporter proteins, GLUT 2 (whic h is the typical glucose transporter in hepatocytes of adult liver) an d the erythroid/brain type glucose transporter GLUT 1 (representing th e typical glucose transporter in fetal liver parenchyma), was studied immunocytochemically during hepatocarcinogenesis in rats at different time points between 7 and 65 wk after cessation of 7-wk administration of 12 mg/kg of body weight of N-nitrosomorpholine p.o. (stop model). Foci of altered hepatocytes excessively storing glycogen (GSF) and mix ed cell foci (MCF) composed of both glycogenotic and glycogen-poor cel ls were present at all time points studied. Seven wk after withdrawal of the carcinogen, GSF were the predominant type of focus of altered h epatocytes. Morphometrical evaluation of the focal lesions revealed th at the number and volume fraction of GSF increased steadily until Wk 6 5. MCF were rare at 7 wk, increased slightly in number and size until Wk 37, but showed a pronounced elevation in their number and volume fr action from Wk 37 to Wk 65. In both GSF and MCF, GLUT 2 was generally decreased or partially absent at all time points. Consequently, foci o f decreased GLUT 2 expression showed a steady increase in number and v olume fraction from Wk 7 to Wk 65. GLUT 1 was lacking in GSF but occur red in some MCF from Wk 50 onward. The liver type glucose transporter GLUT 2 was decreased in all adenomas and hepatocellular carcinomas (HC C). In three of seven adenomas and 10 of 12 carcinomas, expression of GLUT 1 was increased compared with normal liver parenchyma. In two cas es of adenoid HCC, cells of ductular formations coexpressed GLUT 2 and GLUT 1. In contrast normal bile ducts, bile duct proliferations, and cystic cholangiomas expressed only GLUT 1. Seven of 12 HCC contained m any microvessels intensely stained for GLUT 1, a phenomenon never obse rved in normal liver. Whenever adenoid tumor formations occurred, GLUT 1-positive microvessels were located in the immediate vicinity of the se formations. Only in one HCC were such microvessels found in the abs ence of adenoid formations. Our studies indicate that a reduction of G LUT 2 expression occurs already in early preneoplastic hepatic foci an d is maintained throughout hepatocarcinogenesis, including benign and malignant neoplasms. Reexpression of GLUT 1, however, appears in a few MCF and in the majority of adenomas and carcinomas.