Glucagon-like peptide-2 increases dysplasia in rodent models of colon cancer.

Abstract

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.

• Authors: Shivangi Trivedi, Stuart C Wiber, Hala M El-Zimaity, Patricia L Brubaker
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 302 Issue 8 Pg. G840-9 (Apr 15 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22323126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Dcx protein, rat
• Doublecortin Protein
• Glucagon-Like Peptide 2
• Imidazoles
• RNA, Messenger
• beta Catenin
• Dextran Sulfate
• 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
• Azoxymethane

Topics

• Animals
• Azoxymethane (pharmacology)
• Blotting, Western
• Carcinogens (pharmacology)
• Colitis (chemically induced, pathology)
• Colonic Neoplasms (pathology)
• Dextran Sulfate
• Diet, High-Fat (adverse effects)
• Doublecortin Protein
• Glucagon-Like Peptide 2 (pharmacology)
• Imidazoles (pharmacology)
• Immunohistochemistry
• Inflammation (pathology)
• Male
• Mice
• Mice, Inbred C57BL
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Inbred F344
• Real-Time Polymerase Chain Reaction
• beta Catenin (biosynthesis)