BIOCHEMICAL MARKERS ASSOCIATED WITH THE STAGES OF PROMOTION AND PROGRESSION DURING HEPATOCARCINOGENESIS IN THE RAT

Specific biochemical changes occurring during hepatocarcinogenesis have been sought by many investigators. The development of multistage models for hepatocarcinogenesis in the rodent has renewed interest in such marker alterations in preneoplastic as well as neoplastic hepatocytes. Preneoplastic altered hepatic foci (AHF) exhibit specific histomorphologic changes as viewed with tinctorial stains and show a variety of biochemical changes as evidenced by enzyme and immunohistochemistry and by other histochemical markers. During the reversible stage of promotion when AHF are scored by multiple markers, the distribution of markers within these lesions differs with the use of different promoting agents. One interpretation of this finding is that each promoting agent stimulates the replication of a set of initiated cells exhibiting the phenotypic characteristics of a specific programmed phenotype. The same markers score AHF during the stage of progression, but many AHF in this stage are phenotypically heterogeneous, exhibiting in tissue sections a "focus-in-focus" pattern of marker alteration. These latter changes can be correlated with the appearance of karyotypic alterations in preneoplastic hepatocytes. On the other hand, it has been difficult to demonstrate the activation, either mutational or transcriptional, of proto-oncogenes until this stage of progression in rat hepatocarcinogenesis. Thus, a study of biochemical and molecular markers during the stages of hepatocarcinogenesis may lead to a better understanding of potential mechanisms involved in the development of neoplasia through the stages of initiation, promotion, and progression.