Neoplastic progression in experimental hepatocarcinogenesis.

The evolution of cancer through a series of progressive steps is discussed in the rat liver model on the basis of the multi-hit-multi-step hypothesis. The available evidence for this hypothesis is reviewed with special attention to its kinetic aspects. The neoplastic cell stages which can be distinguished during the protracted developmental process leading from the early precancerous foci to the malignant hepatocellular carcinoma are discussed in the light of the histological evidence for step-by-step progression manifested as focus-in-focus lesions. The inducibility of progression of the early precancerous foci to the transplantable neoplastic nodule stage by a new experimental protocol of the initiation-promotion-initiation type is indicative of the operation of a common molecular mechanism, i.e., somatic mutation, during the first and later steps of the carcinogenic process.