Carcinogenesis in euploid cells is a phenomenon characterized by a complex, slowly developing sequence of cellular reactions entrained by a rapid initiating event and culminated by the development of a tumor. Separating the appearance of malignant tumors from the initiating event is a latent period that encompasses a series of phenotypic alterations in the population of cells at risk. The latent period of tumor development has been viewed as a biological phenomenon essential to neoplastic transformation, during which initiated cells progressively develop phenotypic modifications that allow their selective multiplication and facilitate the emergence of more aberrant cells. However, the precise relationships of these phenotyically aberrant preneoplastic cells to the tumorigenic population is not known; some of the preneoplastic populations with variant phenotypes are lineal precursors of the tumorigenic population and some are not. Recent evidence from experimental studies in animals and in cell cultures suggest that many of the newly emerging phenotypes are unrelated to tumorigenicity. It is the goal of this project to define those growth-related phenotypes (expression of selected oncogenes and of selected growth factors and growth factor receptors) that are causally related to tumorigenicity, to distinguish these tumor-related phenotypes from those that reflect cell proliferation or genomic damage nonspecifically, and to attempt to identify and evaluate the abnormality or regulation of the responsible genes. We will perform these studies by the technique of clonal analysis using cultured rat liver epithelial cells (WB-344) which transform after carcinogen exposure and express various aberrant phenotypes before they are able to form tumors (including hepatocellular and biliary carcinomas) in vivo. The first objective will be to identify those phenotypic properties that cosegregate clonally with tumorigenicity among numerous independently derived tumorigenic and nontumorigenic clones. Using this strategy we will attempt to identify those phenotypic properties that are necessary but not sufficient for transformed cells to grow autonomously as a tumor, and to define a group or groups of growth-related phenotypes that endow hepatic epithelial cells with the ability to form tumors in vivo. Once the essential phenotypic components of tumorigenicity are identified we will examine the lineage of tumorigenic cells, using clonal analysis to study the pattern of acquisition of phenotypes that are necessary but not individually sufficient for tumorigenicity.
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