ESCAPE FROM NEGATIVE REGULATION OF GROWTH BY TRANSFORMING GROWTH-FACTOR-BETA AND FROM THE INDUCTION OF APOPTOSIS BY THE DIETARY AGENT SODIUM-BUTYRATE MAY BE IMPORTANT IN COLORECTAL CARCINOGENESIS

There are a number of lines of evidence suggesting that transforming g rowth factor beta (TGFbeta) has an important role in the control of in testinal growth and differentiation. In vivo localization studies show that TGFbeta expression occurs predominantly in the differentiated no n proliferating cells of the intestinal epithelium. The use of an anti sense expression vector for TGFbeta resulted in an increased tumorigen icity in an antisense-transfected cancer cell line. In vitro prolifera tion studies showed colorectal premalignant adenoma cells to be more s ensitive to the growth inhibitory effects of TGFbeta than colorectal c ancer cells. Furthermore the conversion of an adenoma to a carcinoma w as accompanied by a reduced response to the inhibitory effects of TGFb eta. The acquisition of partial or complete resistance to the inhibito ry effects of TGFbeta may be an important late event in colorectal car cinogenesis. Of further interest is the possibility that clonal select ion could occur even more rapidly in colorectal tumour cells which not only had lost response to TGFbeta inhibition but produced TGFbeta and were growth stimulated by it. This could have the advantage of not on ly inhibiting the growth of surrounding less malignantly advanced cell s but of also escaping from their potential growth suppressive influen ce. Carcinogenesis is not, however, simply losing response to negative regulators of growth; the fully malignant cell has to acquire new cha racteristics of invasiveness and metastatic potential. Growth factors including TGFbeta may have a role in the complex cascade of events lea ding to the activation of proteolytic enzymes which are involved in pr ogression to an invasive phenotype. Cell proliferation in the large bo wel, as well as being under the control of endogenous growth factors, is also under the influence of dietary components in the lumen such as the naturally occurring fatty acid sodium butyrate. Sodium butyrate a t physiological concentrations induces apoptosis (programmed cell deat h) in colonic tumour cell lines. Since sodium butyrate occurs naturall y in the colorectum, being produced by bacterial fermentation of dieta ry fibre, it may be involved in the control of cell death in human col orectal epithelium. This could, in part, explain the apparent protecti ve effects of dietary fibre. Clonal evolution and tumour progression i n colorectal carcinogenesis could therefore involve loss of response t o endogenous growth factors such as TGFbeta and an escape from the ind uction of programmed cell death by dietary factors.