Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia

Jean Pierre Raufman, Roxana Samimi, Nirish Shah, Sandeep Khurana, Jasleen Shant, Cinthia Drachenberg, Guofeng Xie, Jürgen Wess, Kunrong Cheng

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Abstract

Colon epithelial cells express and most colon cancers overexpress M 3 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 M 3R-/- 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 F 1.5 mm 3 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 M 3R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M3R and post-M3R signaling are novel therapeutic targets for colon cancer.

Original languageEnglish (US)
Pages (from-to)3573-3578
Number of pages6
JournalCancer Research
Volume68
Issue number10
DOIs
StatePublished - May 15 2008

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Muscarinic M3 Receptors
Colon
Azoxymethane
Muscarinic Receptors
Epithelial Cells
Cell Proliferation
Neoplasms
Colonic Neoplasms
Adenocarcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Raufman, J. P., Samimi, R., Shah, N., Khurana, S., Shant, J., Drachenberg, C., ... Cheng, K. (2008). Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia. Cancer Research, 68(10), 3573-3578. https://doi.org/10.1158/0008-5472.CAN-07-6810

Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia. / Raufman, Jean Pierre; Samimi, Roxana; Shah, Nirish; Khurana, Sandeep; Shant, Jasleen; Drachenberg, Cinthia; Xie, Guofeng; Wess, Jürgen; Cheng, Kunrong.

In: Cancer Research, Vol. 68, No. 10, 15.05.2008, p. 3573-3578.

Research output: Contribution to journalArticle

Raufman, JP, Samimi, R, Shah, N, Khurana, S, Shant, J, Drachenberg, C, Xie, G, Wess, J & Cheng, K 2008, 'Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia', Cancer Research, vol. 68, no. 10, pp. 3573-3578. https://doi.org/10.1158/0008-5472.CAN-07-6810
Raufman, Jean Pierre ; Samimi, Roxana ; Shah, Nirish ; Khurana, Sandeep ; Shant, Jasleen ; Drachenberg, Cinthia ; Xie, Guofeng ; Wess, Jürgen ; Cheng, Kunrong. / Genetic ablation of M3 muscarinic receptors attenuates murine colon epithelial cell proliferation and neoplasia. In: Cancer Research. 2008 ; Vol. 68, No. 10. pp. 3573-3578.
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abstract = "Colon epithelial cells express and most colon cancers overexpress M 3 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 M 3R-/- 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 F 1.5 mm 3 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 M 3R-deficient mice have attenuated epithelial cell proliferation, tumor number, and size. M3R and post-M3R signaling are novel therapeutic targets for colon cancer.",
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