UP-REGULATION OF TRANSFORMING GROWTH-FACTOR-ALPHA EXPRESSION BY TRANSFORMING GROWTH-FACTOR-BETA-1, EPIDERMAL GROWTH-FACTOR, AND N,N-DIMETHYLFORMAMIDE IN HUMAN COLON-CARCINOMA CELLS

This report examines the effects of inhibitors of cell proliferation o n transforming growth factor alpha (TGF-alpha) expression in low-densi ty cultures of poorly (PD) and well-differentiated (WD) human colon ca rcinoma cells, continuously maintained in serum-free medium. In contra st to results in certain untransformed cells, growth inhibitors such a s transforming growth factor beta1 (TGF-beta1) and N,N-dimethylformami de up-regulated TGF-alpha mRNA and protein expression in these human c olon carcinoma cells. Treatment of low-density WD cells with TGF-beta1 (10 ng/ml) resulted in a 1.5-fold increase in TGF-alpha mRNA levels w ithin 4 h of treatment. TGF-alpha mRNA levels increased to 2.7-fold ab ove control values by 48 h after TGF-beta1 addition. Additionally, ove r a TGF-beta1 concentration range of 1-30 ng/ml, TGF-alpha protein lev els were increased by 2-10-fold, despite the fact that the growth of t he WD cells remained inhibited. Although TGF-beta1 control of TGF-alph a expression was altered in these WD colon carcinoma cells, relative t o that in untransformed cells previously examined, the cells retained the ability to up-regulate TGF-alpha expression in an epidermal growth factor-dependent manner. In similarity to the results with TGF-beta1 in WD colon carcinoma cells, the differentiation agent N,N-dimethylfor mamide (0.7%) resulted in an increase of TGF-alpha mRNA of approximate ly 3.8-fold in PD colon carcinoma cells, as well as a 4.4-fold increas e in TGF-alpha protein after 4 days of treatment. These results sugges t that inhibitors of cellular proliferation modulate TGF-alpha express ion in these colon carcinoma cells in an aberrant fashion, compared to that previously reported for specific types of untransformed cells. T he increased production of TGF-alpha by these cells, upon treatment wi th a growth inhibitor, may represent a mechanism by which carcinoma ce lls in vivo can create a growth advantage for surrounding stromal cell s.