The connection between increased secretion of the glucagon-related peptides and the development of intestinal villus hyperplasia was first established following clinical reports of patients with glucagon-secreting tumors who presented with small bowel villus hyperplasia. The group of Dowling and colleagues reported a women who presented with a glucagon-producing tumor of the kidney and small bowel enlargement Endocrine tumour in kidney affecting small bowel structure, motility, and absorptive function. Gut. 1971 12(10):773-82. The intestinal abnormalities receded when the tumor was removed.
A subsequent case of a glucagonoma with villus hyperplasia was reported almost 10 years later, Remarkably, the association of intestinal villus hyperplasia and glucagonoma can be detected by CT scanning, with careful attention to the small bowel epithelium, as reported in Villous hypertrophy of the small bowel in a patient with glucagonoma. J Comput Assist Tomogr. 1983 Apr;7(2):334-7. A third case of glucagonoma and intestinal hyperplasia was diagnosed in a 39 y.o. man with giant duodenal villi, in Glucagonoma syndrome demonstrating giant duodenal villi. Gut. 1984 Jul;25(7):784-9.
These cases stimulated considerable interest in the relationship between increased secretion of intestinal glucagon-related peptides and the response to intestinal injury in both rodents and in human subjects with intestinal disease .
Despite an extensive series of experiments linking increased proglucagon gene expression and increased secretion of the intestinal proglucagon-derived peptides (PGDPs) with experimental intestinal injury , the identity of the specific PGDP with intestinotrophic activity proved elusive. Following the observation that mice harboring subcutaneous glucagonomas exhibited significant villus hyperplasia of the small bowel epithelium, peptide injection experiments identified GLP-2 as the PGDP with significant intestinotrophic activity in vivo Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7911-6.
Byrne and colleagues have reported an additional case of glucagonoma and bowel growth and show for the first time that massively elevated levels of circulating GLP-2 are associated with mucosal hyperplasia in the jejunum. See Intestinal Proliferation and Delayed Intestinal Transit in a Patient with a GLP-1-, GLP-2- and PYY-Producing Neuroendocrine Carcinoma. Digestion. 2001;63(1):61-68
Does GLP-2 stimulate the growth or promote development of tumors?
Given the anti-apoptotic and proliferative actions of GLP-2 on the small bowel, and to a lesser extent on the colon, the effects of GLP-2 on tumor cell growth have been studied in several model systems. Thulesen and colleagues administered native GLP-2 and a GLP-2 analogue to mice following initiation of tumor development with the methylating carcinogen 1,2-dimethylhydrazine (DMH). Mice were treated with GLP-2 for 10 or 30 days, and the number and size of polyps was quantified. Although no difference in survival was noted amongst treatment groups, GLP-2 treatment was associated with increased polyp burden as outlined in Glucagon-like peptide 2 (GLP-2) accelerates the growth of colonic neoplasms in mice. Gut. 2004 Aug;53(8):1145-50. Masur and colleagues examined the proliferative actions of GLP-2, with and without DPP-4 inhibition, using 2 human colon cancer cel lines, SW480 andHT29 cells. The combination of GLP-2 and DPP-4 inhibition increased the proliferation and migration of these cells through incompletely understood mechanisms, as it remains unclear whether these cells express the GLP-2 receptor DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells. Regul Pept. 2006 Dec 10;137(3):147-55.
Analysis of a large number of human tumors for GLP-2R expression by EST analysis demonstrates that the majority of tumors studied to date do not express GLP-2R mRNA transcripts. Koehler and colleagues subsequently examined the proliferative and anti-apoptotic actions of GLP-2 on human colon cancer cell lines transfected with the human GLP-2 receptor; no effect of GLP-2 on cell survival or growth was noted, either in experiments done in vitro, or following implantation of tumor cells into nude mice in vivo. Similarly, chronic treatment of ApcMin/+ mice with GLP-2 did not modify the number or size of polyps, and genetic deletion of the endogenous GLP-2 receptor failed to modify tumor formation in ApcMin/+:Glp2r-/- mice Glucagon-like Peptide-2 Does Not Modify the Growth or Survival of Murine or Human Intestinal Tumor Cells Cancer Res 2008 68: 7897-7904
Bengi and colleagues examined GLP-2R expression in 30 human colorectal cancers and 20 polyps by immunohistochemistry (GLP-2R antibody from Genetex). GLP-2R immunopositivity was detected in enteroendocrine cells of normal mucosa but not in adenomas. Focal GLP-2R immunopositive cytoplasmic staining was detected in 20% of colorectal carcinomas. Does glucagon like peptide-2 receptor expression have any effect on the development of human colorectal cancer? Turk J Gastroenterol. 2011 Aug;22(4):388-94.
In contrast, Iakoubov and colleagues used the model of azoxymethane-induced carcinogenesis to examine the tumor-promoting effects of GLP-2 in mice. Treatment with h(Gly2)-GLP-2 increased the number of aberrant crypt foci and resulted in the development of adenocarcinomas in mice, whereas the GLP-2 receptor antagonist, GLP-2(3-33) reduced the number of aberrant crypt foci Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice. Endocrinology. 2009 Jun 4. [Epub ahead of print]
Korner and colleages used GLP-2 receptor autoradiography to characterize GLP-2 binding sites in human tumors and non-neoplastic human tissues using 2 structurally distinct iodinated GLP-2 peptide ligands. Tissue sections from 237 tumors, 96 non-tumorous tissues, and 52 tissue samples from non-neoplastic GI diseases (Crohns, UC, and Hirschprungs disease) were examined. 15/22 Gastrointestinal stromal tumors (GIST) contained detectable GLP-2 binding sites and 1/7 rhabdomyosarcomas bound ligand; all other gastrointestinal, endocrine, and epithelial tumors were negative for GLP-2 binding (221/237 tumors were negative for GLP-2 ligand binding).GLP-2 binding was also detected in the myenteric plexus, more robustly in sections from human subjects with Crohn's disease. A partial Glp2r cDNA PCR product was also detected in a select number of human tumor specimens.