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Genetic Ablation of M₃ Muscarinic Receptors Attenuates Murine Colon Epithelial Cell Proliferation and Neoplasia

¹ Division of Gastroenterology and Hepatology, VA Maryland Health Care System and Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine; ² Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland; and ³ Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland

Requests for reprints: Jean-Pierre Raufman, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, 22 South Greene Street, N3W62 Baltimore, MD 21201. Phone: 410-328-8728; Fax: 410-328-8315; E-mail: jraufman{at}medicine.umaryland.edu.

Key Words: cell proliferation • colon cancer • muscarinic receptors • acetylcholine • azoxymethane

Colon epithelial cells express and most colon cancers overexpress M₃ muscarinic receptors (M₃R). In human colon cancer cells, post-M₃R signaling stimulates proliferation. To explore the importance of M₃R expression in vivo, we used the azoxymethane-induced colon neoplasia model. Mice treated with weekly i.p. injection of saline [10 wild-type (WT) mice] or azoxymethane (22 WT and 16 M₃R^–/– mice) for 6 weeks were euthanized at 20 weeks. At week 20, azoxymethane-treated WT mice weighed 16% more than M₃R^–/– mice (33.4 grams ± 1.0 grams versus 27.9 grams ± 0.5 grams; mean ± SE, P < 0.001). In azoxymethane-treated M₃R^–/– mice, cell proliferation (BrdUrd staining) was reduced 43% compared with azoxymethane-treated WT mice (P < 0.05). Whereas control mice (both WT and M₃R^–/–) had no colon tumors, azoxymethane-treated WT mice had 5.3 ± 0.5 tumors per animal. Strikingly, azoxymethane-treated M₃R^–/– mice had only 3.2 ± 0.3 tumors per mouse (P < 0.05), a 40% reduction. Tumor volume in azoxymethane-treated M₃R^–/– mice was reduced 60% compared with azoxymethane-treated WT mice (8.1 mm³ ± 1.5 mm³ versus 20.3 mm³ ± 4.1 mm³; P < 0.05). Compared with WT, fewer M₃R^–/– mice had adenomas (6% versus 36%; P = 0.05), and M₃R^–/– mice had fewer adenocarcinomas per mouse (0.6 ± 0.1 versus 1.7 ± 0.4; P < 0.05). Eleven of 22 WT but no M₃R^–/– mice had multiple adenocarcinomas (P < 0.001). Compared with WT, azoxymethane-treated M₃R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M₃R and post-M₃R signaling are novel therapeutic targets for colon cancer. [Cancer Res 2008;68(10):3573–8]