REDUCTION IN TRANSFORMING-GROWTH-FACTOR-BETA TYPE-II RECEPTOR IN MOUSE LUNG CARCINOGENESIS

Transforming growth factor-beta (TGF-beta) is a growth modulator that inhibits the proliferation of many epithelial cells through interactio n with its receptors, the type I and type II receptors (TGF-beta RI an d RII) by activating their serine/threonine kinase activities. Loss of growth inhibition by TGF-beta is thought to contribute to the develop ment of many types of tumors. To examine the roles of TGF-beta 1, -bet a 2, and -beta 3 and TGF-beta RI and RII in chemically induced mouse l ung tumorigenesis, we used immunohistochemical and in situ hybridizati on analyses to measure the expression of their proteins and mRNAs in A /J mice treated with the carcinogen urethane to induce lung adenomas. Immunostaining for the TGF-beta ligands and receptors was detected in the epithelia of the bronchioles of untreated and treated A/J mice at similar levels. Immunostaining for the TGF-beta ligands and receptors was also detected in adenomas by 2 mo. While immunostaining for TGF-be ta 1, -beta 2, and -beta 3 and TGF-beta RI in adenomas was detected at levels comparable to those in bronchioles, immunostaining for TGF-bet a RII was less intense in adenomas than in bronchioles. Decreased immu nostaining for TGF-beta RII in adenomas persisted for at least 8 mo af ter exposure to urethane, whereas immunostaining for TGF-beta 1, -beta 2, and -beta 3 and TGF-beta RI persisted at levels comparable to thos e in normal bronchioles. In situ hybridization studies conducted with TGF-beta receptor riboprobes showed a corresponding reduction in expre ssion of TGF-beta RII mRNA but not of TGF-beta RI mRNA in adenomas com pared with expression in bronchioles. Expression of TGF-beta RII mRNA was also examined in non-tumorigenic and tumorigenic mouse lung cells; expression of TGF-beta RII mRNA was lower in the tumorigenic cells de rived from urethane-induced lung tumors. These data suggest that a dec rease in expression of TGF-beta RII may contribute to autonomous cell growth and may play an important role in mouse lung carcinogenesis ind uced by urethane. (C) 1998 Wiley-Liss, Inc.