Neoplastic Transformation and Defective Control of Cell Proliferation and Differentiation¹

The control of proliferation of nontransformed 3T3 T-proadipocytes in vitro can be mediated at three states in the G₁ phase of the cell cycle. These states are induced by the commitment of cells to differentiate (G_D); by growth factor deprivation at low density or “contact inhibition” at high density (G_S); and by nutrient deprivation (G_N). To determine if neoplastic transformation of proadipocytes is associated with a selective defect in one or more of these G₁ growth arrest processes, we developed and studied eight cloned and several noncloned tumorigenic proadipocyte cell lines. We report that all transformed proadjjipocyte cell lines are tumorigenic and all lack the ability to arrest at G_D and differentiate. By contrast, ∼90% of transformed proadipocyte cell lines retain their ability to growth arrest at G_S at low density when deprived of growth factors, and ∼90% growth arrest at G_N when deprived of nutrients. These observations suggest that neoplastic transformation of proadipocytes is primarily associated with abrogation of growth control mediated at G_D. However, whereas most transformed proadipocytes arrest at G_S at low density when deprived of serum, all transformed proadipocyte cell lines do not efficiently arrest at G_S at high density due to “contact inhibition.” This suggests that neoplastic transformation of proadipocytes results from a primary defect in growth control mediated at G_D and from an additional defect at G_S. These results are discussed with respect to their possible significance for the biological mechanisms of the initiation and promotion of carcinogenesis.