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Angiotensin II Type 2 Receptor Gene Deficiency Attenuates Susceptibility to Tobacco-Specific Nitrosamine-Induced Lung Tumorigenesis: Involvement of Transforming Growth Factor-ß-Dependent Cell Growth Attenuation

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Masaaki Tamura, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, 210 Coles Hall, Manhattan, KS 66506. Phone: 785-532-4825; Fax: 785-532-4557; E-mail: mtamura{at}vet.KSU.edu.

To clarify an involvement of angiotensin II signaling in lung neoplasia, we have examined the effect of angiotensin II receptor deficiency on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)–induced lung tumorigenesis. Male angiotensin II type 2 receptor (AT₂)-null mice with an SWR/J genetic background and control wild-type mice were treated with NNK (100 mg/kg, i.p.) or saline vehicle. NNK treatment caused the development of lung tumors in all wild-type control mice (100 % tumor prevalence), but only 85% of AT₂-null mice developed tumors. The tumor multiplicity in AT₂-null mice (1.9 ± 0.3) was significantly smaller than that in wild-type mice (4.1 ± 0.9). Primary cultured lung fibroblasts prepared from both AT₂-null and wild-type mice markedly increased the colony counts of A549 lung cancer cells in soft agar, but a consistently higher colony count was observed with the wild-type fibroblasts (fold increase in colony number, 5.6 ± 0.5) than with the AT₂-null fibroblasts (3.5 ± 0.8). The underlying mechanism by which angiotensin II regulates cancer cell growth is due to the regulation of active transforming growth factor-ß (TGF-ß) production. Although the total level of TGF-ß was significantly stimulated when A549 cells were cocultured with either type of fibroblasts, the level of active TGF-ß in the conditioned medium was consistently higher with AT₂-null fibroblasts than with wild-type fibroblasts. These results imply that the AT₂ receptor negatively regulates the level of active TGF-ß and thus increases NNK-induced lung tumorigenesis. The AT₂ receptor function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis.