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(American Journal of Pathology. 1999;154:1867-1876.)
© 1999 American Society for Investigative Pathology

Regular Articles

Evidence for Control of Nitric Oxide Synthesis by Intracellular Transforming Growth Factor-ß1 in Tumor Cells

Implications for Tumor Development

Patricia Lagadec*, Stéphane Raynal{dagger}, Blandine Lieubeau{ddagger}, Nathalie Onier*, Laurent Arnoul§, Valérie Saint-Giorgio*, David A. Lawrence{dagger} and Jean-François Jeannin*

From the Cancer Immunotherapy Research Laboratory,*
Ecole Pratique des Hautes Etudes, and INSERM U517, Faculty of Medicine, Dijon, France; CNRS,{dagger}
Villejuif, France; Institute of Biology,{ddagger}
INSERM U419, Nantes, France; and the G.F. Leclerc Anticancer Research Center,§
Dijon, France

Transforming growth factor-ß1 (TGF-ß1) has been shown to down-regulate NO synthesis in a variety of normal cells. In the present study, we investigated the influence of TGF-ß1 upon NO production in tumor cells and its consequences for tumor development. During the growth of PROb colon carcinoma cells intraperitoneally injected in syngeneic BDIX rats, intratumoral concentration of TGF-ß1 increases while NO concentration stays very low. Tumor regression induced by intraperitoneal injections of a lipid A is associated with a decrease in TGF-ß1 and an increase in NO intratumoral concentration. In these tumors, PROb tumor cells are the NO- and TGF-ß1-secreting cells. Using PROb cells transfected with an expression vector coding for TGF-ß1 antisense mRNA, we demonstrate in vitro that there is an inverse correlation between the amount of TGF-ß1 secreted and the ability of PROb cells to secrete NO. As the same results were obtained in the presence of an anti-TGF-ß type II receptor neutralizing antibody, and as exogenous TGF-ß1 is without any effect on NO secretion by PROb cells, TGF-ß1 apparently down-regulates NO synthesis in PROb cells by an intracellular mechanism. These results suggest that endogenous TGF-ß1 constitutes a potential target in a search for new antitumoral agents.




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