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Expression of Growth-related Genes during Tumor Progression in v-raf-transformed Rat Liver Epithelial Cells

Laboratory of Experimental Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland 20892

Clonal cell lines were derived from rat liver epithelial cells following their transformation with either v-raf or v-raf/v-myc. Cells transformed with v-raf alone showed reduced tumor incidence and tumor growth rates when implanted into nude mice, compared to cells also expressing the v-myc oncogene. A series of additional clones isolated from a tumor obtained following inoculation of an athymic nude mouse with the v-raf-transformed rat liver epithelial cells displayed an intermediate range of tumor aggressiveness. These findings indicate that unknown genotypic and/or phenotypic changes occur during tumor formation in vivo, which are required in addition to raf activation for complete expression of the malignant phenotype. This in vitro model of tumor progression was used to examine alterations in the expression of genes related to the growth control of liver epithelial cells, which may be involved in the malignant conversion of the preneoplastic cells. A close association was observed between the increased level of expression of the transforming growth factors and ß₁, the decreased expression of extracellular matrix proteins fibronectin and collagen I, and the tumor aggressiveness (latency/growth rate), suggesting a causal role for these factors in the progression of v-raf-transformed rat liver epithelial cells to the fully malignant phenotype.

¹ Present address: Department of Medical Oncology, Lombardi Cancer Center, Georgetown University, 3800 Reservoir Road, Washington, DC 20007.

² To whom requests for reprints should be addressed, at Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 3C28, NIH, Bethesda, MD 20892.

³ Present address: Toxicology Department, Nestlé Research Centre, PO Box 44, Vers-Chez-Les-Blanc, CH-1000 Lausanne 26, Switzerland.

Received 3/13/90. Accepted 8/31/90.

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