Cell Proliferation and Cell Loss in Progression in Liver Carcinogenesis: A New Hypothesis

Abstract

It is becoming well established that the development of hepatocellular carcinoma in the liver of the rat occurs through a number of steps (8 to 10 or more), some of which involve changes in a rare cell and others the progressive modulation of the phenotype in new hepatocyte populations¹. Two major sequences appear in the majority of the models of liver carcinogenesis^1,2. Sequence A, consisting of initiation and promotion, generates benign focal proliferations of hepatocytes (“clonal nodules”), a very small proportion (1–5%) of which persist². Sequence B, consisting of progression, is the multistep process whereby the first precancerous lesion, the persistent hepatocyte nodule, slowly undergoes a series of changes leading to cancer. This sequence also includes the changes that occur in a bona fide cancer leading to increasing growth, invasion and metastasis². Clearly, sequence B is the most relevant and most critical in the development of cancer. It can occur “spontaneously” and needs no external manipulation and is often not influenced in a major way by promoting environments.