THE ROLE OF GROWTH-REGULATORY ABERRATIONS IN PROGRESSION OF HUMAN COLON-CARCINOMA

Colon carcinoma is a multistage disease. Most malignancies arise from pre-existing benign tumors. Multiple chromosomal defects affecting oncogene and tumor suppressor gene function are associated with disease progression. These aberrations result in an imbalance between the normal positive and negative growth effectors, which contribute further to disease progression. We have studied how changes in the expression of TGFalpha and TGFbeta affect colon carcinoma cell behavior. Overexpression of the stimulatory factor TGFalpha in a relatively benign cell line with weak TGFalpha autocrine activity converted the cell type to an aggressive, progressed phenotype in vivo and in vitro. In contrast, disruption of TGFalpha expression by constitutive expression of TGFalpha antisense RNA in a progressed cell line with a strong, internalized autocrine loop resulted in the development of clones with decreased tumorigenicity in vitro and in vivo. Suppression of the inhibitory effects of TGFbeta by constitutive expression of TGFbeta antisense RNA increased the tumorigenicity of the cell lines in vitro and in vivo. None of these alterations in TGFalpha or TGFbeta expression affected the doubling time of the cells. The changes in tumorigenicity were due to effects on the lag phase of growth. We conclude that TGFbeta functions to maintain the cells in a quiescent state while TGFalpha drives reentry into the cell cycle. We have identified a unique cis-element that mediates TGFalpha autoregulation. The transcription factor binding this element is also involved in the cell-cycle regulation of TGFalpha expression. We hypothesize that this factor may be a convergent point TGFalpha and TGFbeta interact in controlling movement into and out of quiescence.