THE CAPACITY FOR GROWTH-STIMULATION BY TGF-BETA-1 SEEN ONLY IN ADVANCED COLON CANCERS CANNOT BE ASCRIBED TO MUTATIONS IN APC, DCC, P53 OR RAS

Human colon cancer development is associated with the accumulation of mutations and deletions in the suppressor genes DCC, APC and p53 and m utations in the dominant oncogene K-ras, with loss of wild type allele s. In earlier studies we had observed that about half of the resected human colon cancers placed into primary culture were growth stimulated by TGF beta 1. This group included the more advanced cancers which we re either poorly differentiated primary-site cancers or metastases. In contract, the more differentiated colon cancers were inhibited or una ffected by TGF beta 1, indicating that a switch fn response to TGF bet a 1 occurs during colon cancer progression. Different sublines of the HT29 colon carcinoma cell line model the resected cancers, responding to TGF beta 1 by proliferation, inhibition or no growth modulation. Th e current study shows that while the poorly differentiated, TGF beta 1 -stimulated sublines are most tumorigenic, all the sublines have the s ame spectrum of mutations: truncating mutations in both APC (adenomato us polyposis coli) alleles, no activated vas genes, mutated and thus o verexpressed p53, and very low expression of DCC compared to normal co lon cells. Genes other than the four already implicated in colon carci noma evolution are responsible for the mitogenic response to TGF beta 1 found in the more advanced cancers.