Peptide YY and cancer: current findings and potential clinical applications

doi:10.1016/S0196-9781(01)00616-7

Peptides

Volume 23, Issue 2, February 2002, Pages 389-395

https://doi.org/10.1016/S0196-9781(01)00616-7 Get rights and content

Abstract

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.

Introduction

First isolated in 1983, peptide YY (PYY) is a 36 amino acid peptide with tyrosine residues at both C and N-terminals from which it derives its name. Structural analyses have demonstrated approximately 70% homology to neuropeptide Y and pancreatic polypeptide, suggesting a common evolutionary precursor [8]. These three peptides together form the primary members of the so-called Pancreatic Polypeptide (PP) family believed to play an important role in the normal physiology of the brain-gut axis [22]. PP peptides all exhibit C-terminal amidation, a feature common in many biologically active peptides.

PYY co-localizes with glucagon and glucagon-like products within endocrine L cells of the intestinal mucosa and to a lesser extent in alpha cells of the pancreas [22]. Studies in a number of mammals including humans have shown that PYY expression increases sequentially along the length of the intestines [22], [51], with peptide levels in the rectum up to 100-fold greater than in the duodenum [2]. This unique distribution makes PYY an ideal candidate for hormonal regulation of upper gastrointestinal function. In fact, PYY causes decreased gastric acid secretion, delays gastric emptying and slows intestinal transit time [22], [50]. PYY is also known to inhibit exocrine [22], [50] and possibly endocrine functions of the pancreas [42].

Receptors for PYY (designated as Y1, Y2, Y5) have been identified throughout the gastrointestinal tract, including both small bowel and colon mucosal epithelium [22], [38]. These findings raise the possibility that PYY may also exhibit additional actions on gastrointestinal tissues, including regulation of cell growth. Dysregulation of cell growth is most critical in the development and progression of cancer. This review will attempt to summarize the available literature and develop possible correlations between peptide YY and cancer. The potential clinical applications of PYY in malignant disease will also be discussed.

Section snippets

Gastrointestinal (GI) carcinoids

Although PYY was first isolated from normal pig intestinal mucosa, within the same year the peptide was shown by immunohistochemistry to be expressed in human endocrine tumors [51]. PYY-positivity was observed in 15% all of rectal carcinoids examined; however, PYY-cells were far outnumbered by cells staining for other gut hormones. A subsequent study using more specific antibody techniques demonstrated 80% of rectal carcinoids examined were PYY-positive [29]. Nevertheless, within each specimen,

Expression and implications in carcinogenesis

Loss of PYY expression has been postulated to have some significance in the development and progression to adenocarcinoma of the colon.

It has been well-established that colon adenocarcinoma develops over time through a multi-stage process that orginates from adenomatous polyps. An early study compared PYY tissue concentrations in normal colon mucosa, polyps, and adenocarcinomas resected in surgery [1]. PYY content of polyps and carcinomas was significantly lower than in control tissue at all

Pancreatic cancer

In rats, PYY was shown to inhibit cholecystokinin-mediated growth in the normal pancreas, as determined by pancreatic weight, RNA, and DNA content [20]. Therefore it is not unreasonable to suspect that the peptide may exhibit growth regulatory effects in pancreatic cancer cells.

The role of PYY in human pancreatic adenocarcinoma has been been examined both in vitro and in vivo. Despite an early in vitro study which suggested a growth stimulatory effect [45], recent findings support a growth

Mucosal growth in iatrogenic malnutrition

Clinically, chemotherapy and radiation treatment often result in gastrointestinal toxicity, nausea, and vomiting, which limits appetite and predisposes patients to nutritional deficiencies [39], [43]. Total parenteral nutrition (TPN) is often required in patients undergoing treatment or with advanced disease states. Unfortunately, prolonged TPN results in mucosal atrophy which increases risk of infection and other complications [39]; therefore an effective stimulant of mucosal growth is needed

Conclusion

Findings from carcinoid tumors and colorectal adenocarcinoma raise the possibility that alterations in PYY expression may have some relevance in tumor development and progression. Whether this occurs as a primary event or results from malignant changes within the cell needs to be elucidated. Close scrutiny of PYY and its interaction with other gut hormones in pre-malignant cells may provide links to key intracellular events that lead to transformation. PYY has been shown to decrease

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Microarray data of gene expression profiles of CRC from GEO and RNA-sequencing dataset of CRC from TCGA were downloaded. After screening overlapping differentially expressed genes (DEGs) by R software, functional enrichment analyses of the DEGs were performed using the DAVID database. Then, the STRING database and Cytoscape were used to construct a protein–protein interaction (PPI) network and identify hub genes. The receiver operating characteristic (ROC) curves were conducted to assess the diagnostic values of the hub genes. Cox proportional hazards regression was performed to screen the potential prognostic genes. Kaplan-Meier curve and the time-dependent ROC curve were used to assess the prognostic values of the potential prognostic genes for CRC patients.
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Se realizó una búsqueda bibliográfica utilizando Pubmed para artículos relevantes, publicados en inglés sin límite de fechas de publicación. Los estudios que relataban datos sobre cáncer preoperatorio, los casos clínicos y publicaciones sin resumen disponible no fueron incluidos.
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Peptide YY and cancer: current findings and potential clinical applications

Abstract

Introduction

Section snippets

Gastrointestinal (GI) carcinoids

Expression and implications in carcinogenesis

Pancreatic cancer

Mucosal growth in iatrogenic malnutrition

Conclusion

J Surg Res

Gastroenterology

Am J Surg

Life Sci

Nutrition

Regul Pept

J Surg Res Apr

J Surg Res

J Surg Res

Biol Psychiatry

Hum Pathol

Hum Pathol

Am J Surg

J Surg Res

Am J Surg

Regul Pept

Brain Res

Neuropeptides

J Gastrointest Surg

Hum Pathol

J Dairy Sci

Gynecol Oncol

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22–36), for interaction with rat intestinal PYY receptorsdevelopment of analogues with potent in vivo activity in the intestine

J Med Chem

Growth-regulatory effects of sensory neuropeptides, epidermal growth factor, insulin, and somatostatin on the non-transformed intestinal epithelial cell line IEC-6 and the colon cancer cell line HT 29

Scand J Gastroenterol

Regional differences in concentrations of regulatory peptides in human colon mucosal biopsy

Dig Dis Sci

Distribution of PYY receptors in human fat cellsan antilipolytic system alongside the alpha 2-adrenergic system

Am J Physiol