title: Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia.
abstract: Colon epithelial cells express and most colon cancers overexpress M(3) muscarinic receptors (M(3)R). In human colon cancer cells, post-M(3)R signaling stimulates proliferation. To explore the importance of M(3)R 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 M(3)R(-/-) mice) for 6 weeks were euthanized at 20 weeks. At week 20, azoxymethane-treated WT mice weighed approximately 16% more than M(3)R(-/-) mice (33.4 grams +/- 1.0 grams versus 27.9 grams +/- 0.5 grams; mean +/- SE, P < 0.001). In azoxymethane-treated M(3)R(-/-) mice, cell proliferation (BrdUrd staining) was reduced 43% compared with azoxymethane-treated WT mice (P < 0.05). Whereas control mice (both WT and M(3)R(-/-)) had no colon tumors, azoxymethane-treated WT mice had 5.3 +/- 0.5 tumors per animal. Strikingly, azoxymethane-treated M(3)R(-/-) mice had only 3.2 +/- 0.3 tumors per mouse (P < 0.05), a 40% reduction. Tumor volume in azoxymethane-treated M(3)R(-/-) mice was reduced 60% compared with azoxymethane-treated WT mice (8.1 mm(3) +/- 1.5 mm(3) versus 20.3 mm(3) +/- 4.1 mm(3); P < 0.05). Compared with WT, fewer M(3)R(-/-) mice had adenomas (6% versus 36%; P = 0.05), and M(3)R(-/-) mice had fewer adenocarcinomas per mouse (0.6 +/- 0.1 versus 1.7 +/- 0.4; P < 0.05). Eleven of 22 WT but no M(3)R(-/-) mice had multiple adenocarcinomas (P < 0.001). Compared with WT, azoxymethane-treated M(3)R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M(3)R and post-M(3)R signaling are novel therapeutic targets for colon cancer.
authors.affiliation: Division of Gastroenterology and Hepatology, VA Maryland Health Care System and Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA. jraufman@medicine.umaryland.edu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.forename: Roxana
authors.initials: R
authors.lastname: Samimi
authors.forename: Nirish
authors.initials: N
authors.lastname: Shah
authors.forename: Sandeep
authors.initials: S
authors.lastname: Khurana
authors.forename: Jasleen
authors.initials: J
authors.lastname: Shant
authors.forename: Cinthia
authors.initials: C
authors.lastname: Drachenberg
authors.forename: Guofeng
authors.initials: G
authors.lastname: Xie
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Kunrong
authors.initials: K
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D043587:Receptor, Muscarinic M3 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D043587:Receptor, Muscarinic M3; D001397:Azoxymethane