THE QUANTITATION OF ALTERED HEPATIC FOCI DURING MULTISTAGE HEPATOCARCINOGENESIS IN THE RAT - TRANSFORMING GROWTH-FACTOR-ALPHA EXPRESSION ASA MARKER FOR THE STAGE OF PROGRESSION

The experimental three-stage hepatocarcinogenesis protocol of initiati on, promotion, and progression, coupled with the analytical technique of stereology, permits quantitative analysis of the carcinogenic proce ss, including the derivation of biologically based risk assessment mod els. The aberrant expression of the placental isozyme of glutathione S -transferase (PGST) is an efficient marker for initiated, preneoplasti c, and neoplastic hepatocytes. Putatively initiated cells and their cl onal progeny can be identified, enumerated, and their growth character istics determined on the basis of their aberrant expression of this pr otein. A lack of suitable markers has made the identification and quan titation of hepatocytes in the early stage of progression more difficu lt. One characteristic of cells in the stage of progression is the evo lution of relatively autonomous growth. The alteration of growth facto r signalling pathways may provide one mechanism for this observation. The expression of transforming growth factor alpha (TGF alpha) is seen in many malignancies. The initiation-promotion-progression protocol h as been used to induce progression in the rat liver. The focal express ion of TGF alpha was found to correlate with areas of progression in r ats subjected to this protocol. The ability to identify and quantitate cells in the stage of progression should facilitate application of th e Moolgavkar-Venzon-Knudson model for assessing human risk from carcin ogens active at each of these three stages. Validation of this model w ill require determination of the number and growth characteristics of hepatocytes in the stage of progression.