Carcinogen-induced alteration in liver epidermal growth factor receptor distribution during the promotion stage of hepatocarcinogenesis in rat

Changes in hepatic membrane binding capacity for epidermal growth factor (EGF) were assessed during 2-acetylamino-fluorine (2-AAF)-induced hepatocarcinogenesis. An overall decrease in membrane EGF binding levels was observed throughout the period of 2-AAF administration. Immunochemical studies indicated the decreases in EGF binding levels were paralleled by decreases in tissue EGF receptor levels. Immunohistochemical studies showed that the losses in hepatic EGF receptor levels were not uniform throughout the liver during the early, promotion stage of cancer development. During the promotion stage, preneoplastic liver nodules were found to display a higher level of EGF receptor than surrounding hepatic tissue. This resistance to 2-AAF-mediated down-regulation of EGF receptor may confer a proliferative advantage to the developing nodule relative to the surrounding liver tissue. Similar immunochemical and immunohistochemical analysis of hepatocarcinomas at late stages of 2-AAF-induced hepatocarcinogenesis indicated a uniform loss of EGF receptor in tumor and surrounding tissue. These studies indicate that carcinogen-mediated changes in EGF binding levels are different during the multistage process of hepatocarcinogenesis, and that resistance to down-regulation of EGF receptor among preneoplastic nodules may have a role in providing a selective growth advantage to initiated cell populations. EGF receptor may be useful as a dynamic marker assessing the development of hepatic tumors.