peptide-yy and Colonic-Neoplasms

Peptide YY (PYY) is a naturally occurring gut hormone with mostly inhibitory actions on multiple tissue targets. PYY has been identified in several carcinoid tumors and a decreased expression of PYY may be relevant to the development and progression of colon adenocarcinoma. Treatment with PYY decreases growth in pancreatic and breast tumors, most likely through a reduction in intracellular cAMP. In cancer patients, PYY may also improve malnutrition that results from iatrogenic causes or cachexia associated with advanced disease. PYY plays a significant role in multiple aspects of cancer from regulation of cell growth to potential therapeutic applications.

Topics: Adenocarcinoma; Breast Neoplasms; Cachexia; Carcinoid Tumor; Cell Division; Colonic Neoplasms; Cyclic AMP; Humans; Pancreatic Neoplasms; Peptide YY; Time Factors

There is now clear-cut evidence that polypeptide growth factors control the proliferation of the normal gastrointestinal mucosa. Epidermal growth factor (EGF) stimulates normal growth throughout the gastrointestinal tract, and accelerates the healing of ulcerated epithelium. While the effects of gastrin were at first thought to be similarly widespread, the gastrin target now appears to be restricted to the enterochromaffin-like cells in the stomach. Isolated reports suggest that several other hormones, including fibroblast growth factor and the insulin-like growth factors, have similar proliferative effects. In contrast, indirect evidence suggests that somatostatin and transforming growth factor-beta inhibit the growth of the gastrointestinal mucosa. The same growth factors profoundly affect the growth of some gastrointestinal carcinomas. Prolonged hypergastrinaemia increases the risk of development of gastric endocrine tumours, but has no effect on the incidence of gastric adenocarcinoma. Gastrin also stimulates the in vivo growth of 50% of gastric and colorectal carcinoma xenografts, but has no consistent effect on the growth of carcinoma cell lines in vitro. EGF, on the other hand, significantly stimulates proliferation of many gastrointestinal cell lines in culture. Interest has recently focused on autocrine stimulation of gastrointestinal carcinoma growth. Elevated levels of EGF receptor, and of EGF or related mRNAs, have been demonstrated in gastric carcinomas, and the growth of some gastrointestinal cell lines is inhibited by antibodies against EGF, and by antisense oligonucleotides based on EGF mRNA. Similarly gastrin/cholecystokinin antagonists inhibit the growth of several colon carcinoma cell lines, although the spectrum of antagonist potencies suggests that classical gastrin and cholecystokinin receptors are not necessarily involved. Continued research on antagonists may therefore lead to novel therapies for gastrointestinal cancers.

Topics: Adult; Animals; Colonic Neoplasms; Digestive System Physiological Phenomena; Epidermal Growth Factor; ErbB Receptors; Gastrins; Gastrointestinal Hormones; Gastrointestinal Neoplasms; Glucagon-Like Peptides; Humans; Peptide YY; Peptides; Somatostatin; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tumor Cells, Cultured

The gastrointestinal peptide hormones ghrelin and PYY have been shown to play a role in the regulation of metabolism and appetite. We investigate the effect of Biliopancreatic diversion with Roux-en-Y gastric bypass (BPD-RYGBP) on the circulating levels of ghrelin and peptide YY during the first 3 months postoperatively as compared to the effects of colectomy, an abdominal operation of similar severity.. Fasting plasma levels of ghrelin and PYY were determined in 20 super-obese patients (BMI> or =50) who underwent BPD-RYGBP and in 13 patients who underwent colectomy for large bowel cancer. Fasting plasma ghrelin and PYY levels were measured preoperatively and during the postoperative period on days 1, 3, 7, 30 and 90 in all patients of both groups, and at 1 year for 10 of the patients who had attained 1-year follow up.. Preoperatively, both plasma ghrelin and PYY levels were lower in the BPD-RYGBP group of patients. A temporary decrease in plasma ghrelin levels was observed in both groups of patients during the immediate postoperative period, with a gradual return to preoperative levels by the 3rd month. In addition, ghrelin concentrations increased at 1 year to levels 40% higher than those at baseline, in 10 of the BPD-RYGBP patients who had completed the 1-year follow-up (P=0.004). Plasma PYY levels in the colectomy group decreased in the first 3 postoperative days and then returned to baseline. In contrast, PYY levels in the BPD-RYGBP group did not change during the early postoperative period but increased to levels 50% higher at 3 months (P<0.001) and 170% higher at 1 year (P<0.001) than the baseline.. The great postoperative increase in the levels of the anorexigenic peptide PYY following BPD-RYGBP may contribute to the reduced appetite observed after this type of bariatric surgery. The changes in ghrelin levels postoperatively make its contribution to the appetite suppression less likely.

Topics: Adult; Appetite; Biliopancreatic Diversion; Colectomy; Colonic Neoplasms; Female; Gastric Bypass; Ghrelin; Humans; Male; Middle Aged; Obesity, Morbid; Peptide Hormones; Peptide YY; Postoperative Period; Prospective Studies; Radioimmunoassay; Rectal Neoplasms

The hormone PYY (peptide YY), synthesized by endocrine cells in the pancreas, ileum, colon and stomach has widespread inhibitory effects on gastrointestinal and pancreatic fluid secretion. Transgenic mice expressing a viral oncoprotein under the control of the PYY gene 5'-flanking region develop well-differentiated colonic endocrine tumours producing mainly PYY and enteroglucagon. In the present study, we investigated the expression of AQP4 (aquaporin 4) water channel and H(+)/K(+)-ATPase in stomachs from both control and transgenic mice.. Semi-quantitative RT (reverse transcriptase)-PCR showed an increase in the AQP4 transcript compared with control mice. Quantitative Western-blot analysis of stomachs from control and transgenic mice confirmed a significant increase in the 30 kDa AQP4 protein in transgenic mice. In control mice, AQP4 is specifically expressed in the basolateral membrane of gastric parietal cells, located in the basal region of the fundic glands. This particular location suggests that parietal cells in the base region of gastric pits might have a major role in water transport when compared with the more superficial parietal cells. Interestingly, immunofluorescence studies on transgenic mice revealed that the quantitative increase of AQP4 expression was actually due to an increase in the number of AQP4-expressing epithelial cells rather than to a higher expression of AQP4 in parietal cells. In fact, immunofluorescence experiments using the specific antibody raised against the AE2 isoform of Cl(-)/HCO3- exchanger specifically expressed in parietal cells confirmed that the number of parietal cells was comparable in both PYY and control stomachs. Moreover, in transgenic mice, a parallel significant decrease in the expression of H(+)/K(+)-ATPase was observed, as revealed by RT-PCR, quantitative immunoblotting and immunofluorescence.. In the present study, we demonstrate that the sustained inhibition of gastric secretion due to tumours producing PYY/enteroglucagon in transgenic mice is associated with an increase in AQP4 expression and a down-regulation of H(+)/K(+)-ATPase in parietal cells that acquire the characteristics of basal parietal cells. The absence of H2 receptors-mediated signalling due to the inhibition of histamine release from ECL (enterochromaffin-like) cells by PYY may be in part responsible for the observed increase in the number of parietal cells expressing AQP4.

Topics: Animals; Aquaporin 4; Aquaporins; Colonic Neoplasms; Endocrine Gland Neoplasms; Gastric Mucosa; H(+)-K(+)-Exchanging ATPase; Mice; Mice, Transgenic; Peptide YY; Stomach

Colonic carcinoma was induced in male Sprague-Dawley rats by injecting them with 1,2-dimethylhydrazine dihydrochloride. Control rats were injected with EDTA solution. Tissue specimens of colon from four groups of animals: (i) rats without tumour, (ii) with dysplasia and lymphoid hyperplasia, (iii) with colonic adenocarcinoma, and (iv) controls, were investigated. The colonic endocrine cells were detected by immunocytochemistry and quantified by computerised image analysis. Peptide YY (PYY)- and serotonin-immunoreactive cells were found in the colon of all the groups investigated. There were few somatostatin- or enteroglucagon-immunoreactive cells and no pancreatic polypeptide (PP)-immunoreactive cells in the colon of any of the groups studied. The density of PYY-immunoreactive cells increased significantly in rats with dysplasia and lymphoid hyperplasia and in rats with colon carcinoma. There was no statistically significant difference as regards cell secretory index (CSI) or nuclear area of PYY-immunoreactive cells in any of treated groups examined. Nor was there any statistically significant difference between all treated animal groups and controls, as regards cell density, CSI, or nuclear area of serotonin-immunoreactive cells. The present observations in an animal model of human colon carcinoma support the assumption that neuroendocrine peptides in the gut are involved in the carcinogenesis of colorectal carcinoma. However, The nature of the changes in the colonic endocrine cells observed here differed from those in patients with colon carcinoma, possibly due to a difference between the response of young rats to an induced colon carcinoma and a spontaneously developed carcinoma in elderly humans, or due to a species difference.

Topics: 1,2-Dimethylhydrazine; Adenocarcinoma; Animals; Carcinogens; Colon; Colonic Neoplasms; Enteroendocrine Cells; Image Processing, Computer-Assisted; Immunohistochemistry; Male; Peptide YY; Rats; Rats, Sprague-Dawley

Inhibition of apoptosis may allow cells with drug-induced damage to escape programmed cell death. The bcl-2 protein inhibits apoptosis and bcl-2 overexpression has been associated with drug resistance. It is our hypothesis that higher levels of bcl-2 expression will be seen in colon cancer cells resistant to PYY treatment.. Caco2 and HCT116 colon cancer cells were treated with 2 microM PYY for 24 hours. Protein was extracted from cells surviving PYY treatment; bcl-2 expression was measured by enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blotting.. Caco2 and HCT116 cells surviving PYY treatment demonstrated increased bcl-2 from 20.54+/-2.7 to 28.63+/-2.20 units/mL (P <0.05) and 21.98+/-1.28 to 29.32*+/-2.26 units/mL, respectively.. Increased expression of bcl-2 is seen in a population of colon cancer cells resistant to PYY. Hence, bcl-2 may protect neoplastic cells from apoptosis; its levels may be useful in predicting chemotherapy response and in selecting appropriate drug regimens.

Topics: Apoptosis; Blotting, Western; Cell Survival; Colonic Neoplasms; Enzyme-Linked Immunosorbent Assay; Genes, bcl-2; Humans; Peptide YY; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured

The hormone peptide YY is produced by endocrine cells in the pancreas, ileum and colon. We have previously shown that peptide YY is coexpressed in all four islet cell types in the murine pancreas when they first appear, suggesting a common peptide YY-producing progenitor. In the colon, peptide YY has been frequently identified in glucagon-expressing L-type endocrine cells. Characterization of colonic endocrine tumors in transgenic mice expressing simian virus 40 large T antigen under the control of the peptide YY gene 5' flanking region revealed tumor cells producing not only peptide YY and glucagon, but also neurotensin, cholecystokinin, substance P, serotonin, secretin, and gastrin. This suggested that multiple enteroendocrine lineages were related to peptide YY-producing cells. Subsequent examination of the ontogeny of colonic endocrine differentiation in nontransgenic mice revealed that peptide YY was the first hormone to appear during development, at embryonic day 15.5. Between embryonic days 16.5 and 18.5, cells expressing glucagon, cholecystokinin, substance P, serotonin, secretin, neurotensin, gastrin and somatostatin first appeared and peptide YY was coexpressed in each cell type at this time. Peptide YY coexpression continued in a significant fraction of most enteroendocrine cell types throughout fetal and postnatal development and into adulthood, with the exception of serotonin-producing cells. This latter population of cells expanded dramatically after birth with rare coexpression of peptide YY. These studies indicate that expression of peptide YY is an early event in colonic endocrine differentiation and support the existence of a common progenitor for all endocrine cells in the colon.

Topics: Animals; Antigens, Viral, Tumor; Cell Differentiation; Colon; Colonic Neoplasms; Endocrine Gland Neoplasms; Endocrine Glands; Gastrointestinal Hormones; Mice; Mice, Transgenic; Neuropeptides; Peptide Biosynthesis; Peptide YY; Peptides; Rats; Simian virus 40; Stem Cells

1. Confluent epithelial layers of a human adenocarcinoma cell line called Colony-6 have been shown to respond to nanomolar concentrations of vasoactive intestinal polypeptide (VIP), peptide YY (PYY), neuropeptide Y (NPY) and somatostatin (Som). 2. The VIP-induced increase in basal short-circuit current (SCC) was attenuated by basolateral application of Som, PYY or NPY, and also by the Y1-receptor agonist [Leu31,Pro34]NPY, as well as pancreatic polypeptide (PP). High concentrations (0.1-3.0 microM) of NPY(2-36) were effective but the C-terminal fragment NPY(13-36) (0.1-1.0 microM) and desamidoNPY (0.6 microM) were not active. A rank order of agonist EC50 values was: PYY > NPY > [Leu31,Pro34]NPY > PP > NPY(2-36) >> NPY (13-36). 3. Receptors for all these peptides were preferentially located within the basolateral domain. Apical addition of PP (1 microM) and Som (100 nM) had no effect upon basal SCC while apical VIP (10 nM) responses were 18%, and apical PYY (100 nM) were 27% the size of respective basolateral controls (100%). 4. Cross-desensitization was observed between [Leu31,Pro34]NPY (1 microM) and both PYY (100 nM) and PP (1 microM) and between PYY and NPY(2-36) (1 microM), but was not significant between PYY (100 nM) and PP (1 microM). We suggest that either these cells express a single new Y-receptor with an unusual phenotype or that two Y-receptor populations exist in Colony-6 cells.

Topics: Adenocarcinoma; Colon; Colonic Neoplasms; Epithelium; Humans; Neuropeptide Y; Pancreatic Polypeptide; Peptide YY; Peptides; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide Y; Secretory Rate; Sensitivity and Specificity; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

A non-transformed small-intestinal cell line from the rat (IEC-6) and a human colon cancer cell line (HT 29) were examined for their trophic response to sensory neuropeptides. Substance P, neurokinin A (NKA), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and peptide YY (PYY) were tested. Epidermal growth factor (EGF), insulin, and somatostatin-14 were also used. Interaction studies were performed on IEC-6 cells by combining EGF or insulin with somatostatin-14. The sensory neuropeptides had no effect either on IEC-6 cell growth and DNA synthesis or on HT29 cell growth. EGF and insulin stimulated cell growth and DNA synthesis in IEC-6 cells and cell growth in HT 29 cells in a dose-dependent fashion. Somatostatin-14 had no effect either alone or in combination with EGF or insulin on IEC-6 cell growth and DNA synthesis. HT 29 cell growth was inhibited by somatostatin-14 only in the presence of serum with a maximal and significant response at 10(-7) M. Our observations suggest that the sensory neuropeptides do not exert a direct growth-regulatory effect either on IEC-6 cells or on HT 29 cells. Somatostatin, however, inhibits serum-induced HT 29 cell growth but does not interfere directly with the proliferative effect of serum, EGF, or insulin on IEC-6 cells in this model.

Topics: Animals; Calcitonin Gene-Related Peptide; Cell Division; Cell Line, Transformed; Cell Transformation, Neoplastic; Cells, Cultured; Colonic Neoplasms; DNA, Neoplasm; Dose-Response Relationship, Drug; Epidermal Growth Factor; Epithelium; Gastrointestinal Hormones; Humans; Insulin; Intestinal Mucosa; Intestines; Neurokinin A; Neurons, Afferent; Neuropeptides; Peptide YY; Peptides; Rats; Somatostatin; Substance P; Transforming Growth Factor beta; Vasoactive Intestinal Peptide

The aim of endoscopic polypectomy is to prevent colorectal cancer, as it is assumed that most, if not all, large bowel cancers are derived from adenomatous polyps. While it is now recognized that colonic endocrine cells, like other mucosal epithelial cells, have an endodermal origin, they are relatively sparse components of large bowel tumors. Peptide YY (PYY) is the most abundant endocrine regulatory peptide localized to the distal bowel. Endocrine cells, like the other cells of the mucosal epithelia, are derived from a common stem cell in the base of the crypts. The presence of endocrine peptides may thus be viewed as a marker for cellular differentiation in the gut. PYY was therefore measured in colonic carcinomas and adenomatous polyps, as its absence would be evidence in favor of genetic alterations in epithelial stem cell maturation. PYY concentrations in extracts of surgically removed colonic carcinomas (n = 22) from all regions were very low compared with those of adjacent normal bowel. Similarly, PYY concentrations in extracts of polyps (n = 39) obtained during endoscopic polypectomy were also very low when compared with those of adjacent normal mucosa. These varied between 1 and 11% of the normal epithelial content, depending upon the region. Low PYY levels appeared to reflect the malignant potential of these lesions: highest in tubular polyps, lower in villous polyps, and lowest in carcinomas. The very low concentrations of PYY in adenomatous polyps, like those of colonic cancer, are consistent with epithelial dysplasia and the incomplete formation of mucosal endocrine cells. These findings support the hypothesis of an adenoma to carcinoma sequence in colonic cancer.

Topics: Adenoma; Carcinoma; Colonic Neoplasms; Colonic Polyps; Humans; Intestinal Mucosa; Osmolar Concentration; Peptide YY; Peptides; Radioimmunoassay

Topics: Adult; Colectomy; Colitis, Ulcerative; Colonic Neoplasms; Fasting; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide YY; Peptides; Radioimmunoassay; Rectal Neoplasms

Peptide YY (PYY)-like immunoreactivity was detected in the mucosa and muscle layer of normal human colon and rectum and in well to moderately differentiated adenocarcinoma derived from the mucosa of the colon and rectum, using a sensitive and specific radioimmunoassay for PYY. The content of PYY-like immunoreactivity in the mucosa was markedly higher than those in the muscle layer and adenocarcinomatous tissue of any part of the colon and rectum. A high concentrations of PYY-like immunoreactivity was demonstrated throughout the colon mucosa (ascending colon 94.14 +/- 15.34 pmol/g, transverse colon 137.19 +/- 13.44 pmol/g, descending colon 168.89 +/- 15.63 pmol/g, and sigmoid colon 223.69 +/- 35.31 pmol/g), the highest being observed in the rectum (313.15 +/- 45.90 pmol/g). The major molecular form of PYY-like immunoreactivity both in the mucosa and muscle layer of normal human colon and rectum and in adenocarcinomatous tissue was judged by gel exclusion chromatography to be identical to pure porcine PYY. This study revealed the presence of PYY-like immunoreactivity not only in normal tissue of the colon and rectum but also in adenocarcinomas with the same elution pattern, and the mucosal concentrations of PYY-like immunoreactivity were found to be increasing distally throughout the colon and rectum.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibody Specificity; Chromatography, Gel; Colon; Colonic Neoplasms; Female; Humans; Intestinal Mucosa; Male; Middle Aged; Muscle, Smooth; Peptide YY; Peptides; Radioimmunoassay; Rectum; Reference Values; Tissue Distribution; Tissue Extracts