During the previous period of support we established 25 human colon carcinoma cell lines from 20 primary tumor specimens. The cell lines had diverse biological properties which were reflective of the inter and intratumoral heterogeneity associated with this disease in humans. The cell lines were divided into 3 groups on the basis of biological and biochemical properties. Group I was highly aggressive and undifferentiated while Group III lines were relatively indolent and differentiated. Group II lines had intermediate properties. Transforming growth factors (TGF) and factors which inhibited anchorage independent growth (TIF) of malignant cells were isolated from a Group II colon carcinoma cell line. These factors showed selective activity towards Group III (TGF and TIF) and Group II (TIF) lines, but had no activity with Group I lines. These results suggest that the heterogeneity of human colon carcinoma is due at least in part to the ability to express or respond to a specific balance of endogenous stimulatory and inhibitory factors. In other work utilizing model systems of malignant mouse cells with well-characterized growth controls involving TGF's we showed that differentiation agents like N,N-dimethylformamide (DMF) and retinoic acid (RA) eliminate RGF sensitivity and alter growth factor expression while re-establishing normal growth controls to the treated malignant cells. During the next period of support we propose to determine the relationship between the biological phenotype of colonic carcinoma cells and growth factors. The types of factors produced by each of the groups will be determined. The sensitivity of the groups to each factor isolated will be determined. Finally, the modulation of the biological properties of colon carcinoma cell lines by DMF, RA and TIF will be related to alterations in factor expression and/or sensitivity.
