glucagon-like-peptide-2 and Cell-Transformation--Neoplastic

Glucagon-like peptide-2 (GLP-2) is a gastrointestinal hormone with intestinotrophic and antiapoptotic effects. The hormone's therapeutic potential in intestinal diseases and relation to intestinal neoplasia has raised great interest among researchers. This article reviews and discusses published experimental and clinical studies concerning the growth-stimulating and antiapoptotic effects of GLP-2 in relation to intestinal neoplasia.. The data used in this narrative review were collected through literature research in PubMed using English keywords. All studies to date examining GLP-2's relation to intestinal neoplasms have been reviewed in this article, as the studies on the matter are sparse.. GLP-2 has been found to stimulate intestinal growth through secondary mediators and through the involvement of Akt phosphorylation. Studies on rodents have shown that exogenously administered GLP-2 increases the growth and incidence of adenomas in the colon, suggesting that GLP-2 may play an important role in the progression of intestinal tumors. Clinical studies have found that exogenous GLP-2 treatment is well tolerated for up to 30 months, but the tolerability for even longer periods of treatment has not been examined.. Exogenous GLP-2 is currently available as teduglutide for the treatment of short bowel syndrome. However, the association between exogenous GLP-2 treatment and intestinal neoplasia in humans has not been fully identified. This leads to a cause for concern regarding the later risk of the development or progression of intestinal tumors with long-term GLP-2 treatment. Therefore, further research regarding GLP-2's potential relation to intestinal cancers is needed.

Topics: Animals; Cell Proliferation; Cell Transformation, Neoplastic; Glucagon-Like Peptide 2; Humans; Intestinal Mucosa; Intestinal Neoplasms

Glucagon-like peptide-2 (GLP-2) is a peptide hormone with multiple beneficial effects on the intestine, including expansion of the mucosal surface area through stimulation of crypt cell proliferation, as well as enhancement of nutrient digestion and absorption. Recent advances in clinical trials involving GLP-2 necessitate elucidation of the exact signaling pathways by which GLP-2 acts. In particular, the GLP-2 receptor has been localized to several intestinal cell types that do not include the proliferating crypt cells, and the actions of GLP-2 have thus been linked to a complex network of indirect mediators that induce diverse signaling pathways. The intestinotropic actions of GLP-2 on the colon have been shown to be mediated through the actions of keratinocyte growth factor and insulin-like growth factor (IGF)-2, whereas small intestinal growth has been linked to IGF-1, IGF-2, and ErbB ligands, as well as the IGF-1 receptor and ErbB. The cellular source of these mediators remains unclear, but it likely includes the intestinal subepithelial myofibroblasts. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are dependent on vasoactive intestinal polypeptide released from submucosal enteric neurons and nitric oxide, respectively. Finally, recent studies have suggested that GLP-2 not only modulates intestinal stem cell behavior but may also promote carcinogenesis in models of sporadic colon cancer. Further consideration of the molecular cross-talk and downstream signaling pathways mediating the intestinotropic effects of GLP-2 is clearly warranted.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Cell Transformation, Neoplastic; Colonic Neoplasms; Fibroblast Growth Factor 7; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; Humans; Intestinal Mucosa; Intestines; Mice; Nitric Oxide; Rats; Receptors, Glucagon; Signal Transduction; Somatomedins; Stem Cells; Vasoactive Intestinal Peptide

APC mutations drive human colorectal cancer (CRC) development. A major contributing factor is colonic stem cell (SC) overpopulation. But, the mechanism has not been fully identified. A possible mechanism is the dysregulation of neuroendocrine cell (NEC) maturation by APC mutations because SCs and NECs both reside together in the colonic crypt SC niche where SCs mature into NECs. So, we hypothesized that sequential inactivation of APC alleles in human colonic crypts leads to progressively delayed maturation of SCs into NECs and overpopulation of SCs. Accordingly, we used quantitative immunohistochemical mapping to measure indices and proportions of SCs and NECs in human colon tissues (normal, adenomatous, malignant), which have different APC-zygosity states. In normal crypts, many cells staining for the colonic SC marker ALDH1 co-stained for chromogranin-A (CGA) and other NEC markers. In contrast, in APC-mutant tissues from familial adenomatous polyposis (FAP) patients, the proportion of ALDH+ SCs progressively increased while NECs markedly decreased. To explain how these cell populations change in FAP tissues, we used mathematical modelling to identify kinetic mechanisms. Computational analyses indicated that APC mutations lead to: 1) decreased maturation of ALDH+ SCs into progenitor NECs (not progenitor NECs into mature NECs); 2) diminished feedback signaling by mature NECs. Biological experiments using human CRC cell lines to test model predictions showed that mature GLP-2R+ and SSTR1+ NECs produce, via their signaling peptides, opposing effects on rates of NEC maturation via feedback regulation of progenitor NECs. However, decrease in this feedback signaling wouldn't explain the delayed maturation because both progenitor and mature NECs are depleted in CRCs. So the mechanism for delayed maturation must explain how APC mutation causes the ALDH+ SCs to remain immature. Given that ALDH is a key component of the retinoic acid (RA) signaling pathway, that other components of the RA pathway are selectively expressed in ALDH+ SCs, and that exogenous RA ligands can induce ALDH+ cancer SCs to mature into NECs, RA signaling must be attenuated in ALDH+ SCs in CRC. Thus, attenuation of RA signaling explains why ALDH+ SCs remain immature in APC mutant tissues. Since APC mutation causes increased WNT signaling in FAP and we found that sequential inactivation of APC in FAP patient tissues leads to progressively delayed maturation of colonic ALDH+ SCs, the hypothesis

Topics: Adenomatous Polyposis Coli; Adult Stem Cells; Aldehyde Dehydrogenase 1 Family; Animals; Biomarkers; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromogranin A; Colon; Colorectal Neoplasms; Feedback, Physiological; Genes, APC; Glucagon-Like Peptide 2; Glucagon-Like Peptide-2 Receptor; HCT116 Cells; HT29 Cells; Humans; Mice; Models, Genetic; Mutation; Neuroendocrine Cells; Receptors, Somatostatin; Signal Transduction; Somatostatin; Stem Cell Niche; Tretinoin; Wnt Signaling Pathway