Glucagon-like peptide-2 increases dysplasia in rodent models of colon cancer.
The intestinal hormone, glucagon-like peptide-2 (GLP-2), enhances intestinal growth and reduces inflammation in rodent models. Hence, a degradation-resistant GLP-2 analog is under investigation for treatment of Crohn's disease. However, GLP-2 increases colonic dysplasia in murine azoxymethane (AOM)-induced colon cancer. Considering the increased colon cancer risk associated with chronic colitis, we have therefore examined the effects of long-acting hGly(2)GLP-2, as well as of endogenous GLP-2 using the antagonist hGLP-2(3-33) in two novel models of inflammation-associated colon cancer: rats fed the carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and a high-fat diet (HFD) for one or three cycles, and mice with chronic dextran sodium-sulfate (DSS)-induced colitis administered AOM. hGly(2)GLP-2 treatment of one-cycle PhIP/HFD rats increased the number of colonic aberrant crypt foci by 72 ± 11% (P < 0.01). Fifty-one weeks after three PhIP/HFD cycles, hGly(2)GLP-2-treated rats had a 22% incidence of colon cancer, compared with 0% in vehicle-treated rats. AOM-DSS mice treated with vehicle or hGly(2)GLP-2 had high-grade dysplasia/colon cancer incidences of 56 and 64%, respectively, compared with 46% in hGLP-2(3-33)-treated AOM-DSS animals (P < 0.05). Unexpectedly, hGLP-2(3-33) also reduced the colitis damage score by 32.0 ± 8.4% (P < 0.05). All high-grade dysplastic/cancerous tumors had nuclear localization of β-catenin although β-catenin mRNA transcript and protein levels did not differ between treatment groups. GLP-2 receptor mRNA expression also was not different. However, hGLP-2(3-33)-treated mice had markedly reduced numbers of doublecortin-and-calmodulin-kinase-like-1-positive stem cells, by 73.7 ± 8.6% (P < 0.05). In conclusion, the results of this study indicate a role for hGly(2)GLP-2 and endogenous GLP-2 as potential cancer promoters in rodents.
Department of 1Physiology, University of Toronto, Toronto, Ontario, Canada.
Shivangi
S
Trivedi
Stuart C
SC
Wiber
Hala M
HM
El-Zimaity
Patricia L
PL
Brubaker
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D003110:Colonic Neoplasms / Q000473:pathology*; D016264:Dextran Sulfate; D059305:Diet, High-Fat / Q000009:adverse effects; D000089662:Doublecortin Protein; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D051176:beta Catenin / Q000096:biosynthesis
D002273:Carcinogens; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D053767:Glucagon-Like Peptide 2; D007093:Imidazoles; D012333:RNA, Messenger; D051176:beta Catenin; D016264:Dextran Sulfate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001397:Azoxymethane