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Glucagon-like Peptide-2 Does Not Modify the Growth or Survival of Murine or Human Intestinal Tumor Cells

Department of Medicine, and the Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Daniel J. Drucker, Mt. Sinai Hospital, SLRI 60 Murray Street, Toronto, Ontario, Canada M5T 3L9. Phone: 416-361-2661; Fax: 416-361-2669; E-mail: d.drucker{at}utoronto.ca.

Key Words: growth factor • peptide hormone • receptor

Glucagon-like peptide-2 (GLP-2) secreted from enteroendocrine cells exerts proabsorptive, regenerative, and cytoprotective actions in the normal and injured gut epithelium. Hence, sustained GLP-2 receptor (GLP-2R) activation represents a strategy under investigation for the prevention and treatment of chemotherapy-induced mucositis. Nevertheless, the consequences of increased GLP-2R signaling for the growth and survival of intestinal tumor cells remain poorly understood. We studied the proliferative and cytoprotective actions of GLP-2 in human colon cancer cells stably transfected with the GLP-2R and in nude mice harboring GLP-2R⁺ human colon cancer cells. The importance of the GLP-2R for tumor growth was also examined in Apc^Min/+ mice chronically treated with exogenous GLP-2 and in Apc^Min/+:Glp2r^–/– mice. GLP-2 increased cyclic AMP accumulation and produced cell-specific activation of growth and survival pathways in DLD-1, SW480, and HT29 cells. However, GLP-2 did not stimulate cell growth or attenuate cycloheximide-, LY294002-, indomethacin-, or chemotherapy-induced cytotoxicity in vitro. Moreover, chronic GLP-2 administration had no effect on the growth of human colon cancer cell xenografts in nude mice in vivo. Daily GLP-2 treatment for 7 weeks increased growth of normal gut mucosa but did not increase the number or size of polyps in Apc^Min/+ mice, and genetic disruption of the Glp2r gene in Apc^Min/+ mice did not modify polyp size or number. Taken together, although GLP-2R activation engages signaling pathways promoting cell proliferation and cytoprotection in the normal gut epithelium, sustained direct or indirect modulation of GLP-2R signaling does not modify intestinal tumor cell growth or survival. [Cancer Res 2008;68(19):7897–904]

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