Evidence for control of nitric oxide synthesis by intracellular transforming growth factor-beta 1 in tumor cells - Implications for tumor development

Transforming growth factor-beta 1 (TGF-beta 1) has been shown to down-regul ate NO synthesis in a variety of normal cells. In the present study, we inv estigated the influence of TGF-beta 1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon ca rcinoma cells intraperitoneally injected in syngeneic BDM rats, intratumora l concentration of TGF-beta 1 increases while NO concentration stays very l ow. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-beta 1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-beta 1-secreting cells. Using PROb cells transfected with an expression vector c oding for TGF-beta 1 antisense mRNA, we demonstrate in vitro that there is an inverse correlation between the amount of TGF-beta 1 secreted and the ab ility of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-beta type II receptor neutralizing antibody, and a s exogenous TGF-beta 1 is without any effect on NO secretion by PROb cells, TGF-beta 1 apparently down-regulates NO synthesis in PROb cells by an intr acellular mechanism. These results suggest that endogenous TGF-beta 1 const itutes a potential target in a search for new antitumoral agents.