Ghrelin in neuroendocrine tumors

Abstract

Ghrelin is a 28 amino acid peptide, primarily produced by the oxyntic mucosa X/A like neuroendocrine cells in the stomach. It is also found in the small intestine, hypothalamus, pituitary gland, pancreas, heart, adipose tissue, and immune system. In gastrointestinal neuroendocrine tumors (NETs) ghrelin release has been well documented. Ghrelin is a brain-gut circuit peptide with an important role in the physiological regulation of appetite, response to hunger and starvation, metabolic and endocrine functions as energy expenditure, gastric motility and acid secretion, insulin secretion and glucose homeostasis, as well as in the potential connection to the central nervous system. Recently, there has been a significant interest in the biological effects of ghrelin in NETs. In this article, we present a comprehensive review of ghrelin's expression and a brief summary of ghrelin's physiological role in NETs patients with carcinoids, type A chronic atrophic gastritis (CAG), with or without MEN-1, and with and without liver metastases. We hope, with the research reviewed here, to offer compelling evidence of the potential significance of ghrelin in NETs, as well as to provide a useful guide to the future work in this area.

Fig. 1.

A proposed pathway of acyl ghrelin, its modification by GOAT and action through the GHS-R1a receptor in the hypothalamus contributing to increase in food intake, GH release, and fat oxidation. Currently, the receptor for desacyl ghrelin has not been discovered.

Fig. 2.

Proposed effects of ghrelin release from neuroendocrine tumors on the regulatory pathways for appetite control. Under normal physiology ghrelin is released during periods of low-protein diet and fasting states. Inhibitory signals such as somatostatin, high fat diet, while inhibited by somatostatin, feeding, high fat diets, feeding, vagal tone, growth hormone, and Interleukin 1β inhibits this release of ghrelin. However, with neuroendocrine tumors, the release of ghrelin from the tumors is not subject to these same regulatory controls.

Fig. 3.

Plot of serum ghrelin against body weight in patients with NETs with (diamond) and without (square) hepatic metastases. Patients with hepatic metastases (blue line) had greater levels of ghrelin, correlating with increase in body weight, compared to patients without hepatic metastases (gray line). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)