It is proposed to continue to delineate the sequence of relevant biological, biochemical and molecular alterations in cells and cell populations that are fundamental to the development of liver cancer with chemicals. Emphasis in the next phase of the proposed study is to be placed on (a) testing the hypothesis that the biochemical or molecular basis for initiation of hepatocellular carcinoma from hepatocytes with selecte chemical carcinogens in the resistant hepatocyte model is fundamentally different than the basis for the selection or promotion of initiated cells by carcinogens; (b) the pursuit and greater depth of the fundamental basis for the resistant of putative preneoplastic hepatocytes to the inhibitory effects of carcinogens on cell proliferation (c) the exploration of the biological behaviour and subsequently the biochemical properties of individual persistant hepatocytes nodules (so-called hyperplastic or neoplastic nodules), one or more of which are known to be one site of origin for hepatocellular carcinoma and (d) the development of reliable makers to distinguish remodelling nodules from persistent nodules and the possible subset of persistent more closely related to cancer as precursors. A variety of methodologic approaches will be used. Although the major emphasis will be on in vivo studies, an increasing number of studies in vitro and using transfer of cells from one animal to another will be undertaken. In this respect, transfer of cells from individual nodules to the spleens of syngeneic animals and the growth in tissue culture of individual persistent nodules will be important foci.
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