Gastrins, iron homeostasis and colorectal cancer

Abstract

The peptide hormone gastrin has been identified as a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. The importance of gastric acid in the absorption of dietary iron first became evident 50 years ago when iron deficiency anemia was recognized as a long-term consequence of partial gastrectomy. This review summarizes the connections between circulating gastrins, iron status and colorectal cancer. Gastrins bind two ferric ions with micromolar affinity and, in the case of non-amidated forms of the hormone, iron binding is essential for biological activity in vitro and in vivo. The demonstration of an interaction between gastrin and transferrin by biochemical techniques led to the proposal that gastrins catalyze the loading of transferrin with iron. Several lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron overload disease hemochromatosis and that transferrin saturation positively correlates with circulating gastrin concentration, suggest the potential involvement of gastrins in iron homeostasis. Conversely, recognition that ferric ions play an unexpected role in the biological activity of gastrins may assist in the development of useful therapies for colorectal carcinoma and other disorders of mucosal proliferation in the gastrointestinal tract. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.

Figure 1. Gastrin Processing

Preprogastrin (101 amino acids) is converted to progastrin (80 amino acids) by removal of its signal peptide (black box). The sequential action of prohormone convertases and carboxypeptidase E then converts the prohormone to glycine-extended forms such as glycine-extended gastrin₃₄ (progastrin_38–72) and glycine-extended gastrin₁₇ (progastrin_55–72, Ggly). The extent of transamidation of glycine-extended gastrin₃₄ to amidated gastrin₃₄ by peptidyl α–amidating monooxygenase is dependent on the tissue. Finally amidated gastrin₃₄ is cleaved to amidated gastrin₁₇ (Gamide) by prohormone convertases. The amino acid sequence of Gamide is ZGPWLEEEEEAYGWMDFamide, where Z represents a pyroglutamate residue. Both non-amidated and amidated forms of gastrin are independently active via different receptors. The CCK2 receptor recognises the amidated C-terminal tetrapeptide of gastrin [15], while the Ggly receptor recognises the ferric ion complexes of the central heptapeptides LEEEEEA and EEEEEAY [77].

Figure 2. Physiological Actions of Progastrin-derived Peptides

Gamide is now recognised as the primary stimulant of gastric acid secretion. Gamide is released from the gastric antral mucosa into the circulation, binds to CCK2 receptors (CCK2R) on ECL cells in the gastric fundic mucosa, and stimulates histamine release. Histamine together with gastrin then stimulates the release of acid from fundic parietal cells. Ggly alone is unable to stimulate acid secretion but potentiates acid release in response to Gamide. The abundant evidence that Gamide acts as a growth factor in the gastric mucosa has been reviewed previously [7]. Gamide was recently shown to increase expression of the gastrin gene via a CCK2 receptor-dependent (CCK2R dep^t) autocrine loop [16]. In contrast the trophic effects of non-amidated gastrins like progastrin and Ggly are principally seen in the colon. In mice overexpression of progastrin or Ggly increases the basal proliferation rate in the colonic mucosa [18]. In rats, short-term administration of Ggly after colostomy to create a defunctioned rectum caused an increase in the proliferation of the rectal mucosa [20]. The stimulation of proliferation in both models is blocked by the chelating agent desferrioxamine, presumably by removal of ferric ions [78]. Progastrin [23, 24] and Ggly [25] do not bind to the CCK2 receptor, but the stimulatory effects of progastrin on proliferation in mouse colonic mucosa are not observed in Cck2r^−/− mice [91].

Figure 3. A Possible Dual Role for Gastrin in Iron Homeostasis and Colorectal Cancer

The first role of gastrins in the stomach is well-established. Following a meal, Gamide is released from the gastric antral mucosa into the circulation and stimulates the release of histamine from ECL cells in the gastric fundic mucosa. Histamine together with gastrin then stimulates fundic parietal cells to release acid into the gastric lumen. Ggly alone is unable to stimulate acid secretion but potentiates acid release in response to Gamide. Presumably the potentiation of acid release will, like the other biological activities of Ggly, be dependent on ferric (Fe³⁺) ions. The acid released will compete for iron-binding sites present in dietary components, and hence increase the concentration of soluble Fe³⁺ ions passing into the duodenum. The cytochrome-b-like ferric reductase Dcytb, present on the villi of duodenal enterocytes, reduces Fe³⁺ to ferrous (Fe²⁺) ions, which are then transported into the enterocyte by the divalent metal ion transporter DMT-1. Fe²⁺ ions are exported into the circulation by ferroportin, and the iron regulator hepcidin controls iron export by formation of a complex with ferroportin. Internalisation and degradation of the complex reduces the amount of ferroportin on the cell surface, and hence reduces iron export. The exported Fe²⁺ ions are then re-oxidised to Fe³⁺ ions by hephaestin. The second postulated role of gastrins increases the availability of iron in the circulation. Circulating Ggly and Gamide will bind Fe³⁺ ions, and the resultant complex will catalyse the loading of apo-transferrin with iron, and hence increase the tissue availability of iron. A like process may also occur within CRC, where the non-amidated gastrins produced by the tumour will similarly catalyse the loading of apo-transferrin (ApoTf) with iron for subsequent uptake by CRC cells. The stimulation of tumour growth by non-amidated gastrins will result from a combination of the enhanced availability of Fe-transferrin (FeTf) and of direct effects on the tumour cells, with the relative importance of the two components as yet undefined.