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The ability of the gastric hormone gastrin to stimulate gut epithelial cell proliferation has been appreciated since the late 1960s.1 However, aside from the special case of gastric carcinoid tumours arising from enterochromaffin-like cells, the contribution of gastrin to gastrointestinal neoplasia has been uncertain. Several developments now suggest a role for gastrin in both gastric and colorectal cancer. In the case of gastric cancer, recent evidence indicates a synergy between gastrin andHelicobacter infection in accelerating progression to atrophy and cancer.2 Different issues are involved in colorectal cancer. The important emerging concepts here are that (a) the gastrin gene is expressed in colorectal cancer cells, but (b) the main products of gene expression in these cells are not ligands for the gastrin-cholesystokinin receptor B (CCKB), although (c) they do act as colon growth factors. The paper by Smith and Watson3 now shows that gastrin mRNA, detected by reverse transcription-polymerase chain reaction, is expressed in early stage polyps, that the main forms of gastrin detected by immunohistochemistry are biosynthetic precursor peptides, and that there is also parallel expression of the gastrin-CCKB receptor (see page 820).
It used to be thought that the only biologically active peptides generated from the gastrin gene were COOH terminally amidated peptides such as G34 and G17, and that carboxy terminal amidation was essential for the biological activity of members of the gastrin family. The amidated gastrins are generated from a precursor, progastrin, via biosynthetic intermediates, the Gly-gastrins (fig 1). Neither progastrin nor Gly-gastrins have a carboxy terminal amide group and therefore they do not have high affinity for the gastrin-CCKB receptor, which is the receptor mediating acid secretory responses to gastrin. It seems, however, that these peptides exhibit other biological properties, notably stimulation of colon cell growth. This effect has been found in both transgenic mice over expressing progastrin and Gly-gastrin, and in colon cancer cell lines.4-6 The precise receptors mediating the trophic actions of progastrin and Gly-gastrin remain uncertain. It is not clear if there is one (the putative gastrin-CCKC receptor) or several. It is conceivable that a modified version of the gastrin-CCKB receptor, perhaps generated by alternative mRNA splicing, mediates the effects of progastrin and Gly-gastrin; at present this idea is largely speculative. It is unlikely, however, that the progastrin and Gly-gastrin found by Smith and Watson in early stage polyps act at authentic gastrin-CCKB receptors.
The pattern of relatively high abundance of progastrin and Gly-gastrin compared with amidated gastrin that occurs in colonic neoplasms differs markedly from that in normal pyloric antral G cells where the amidated gastrins predominate. There are several plausible explanations for this. There may, for example, be differences in the expression of enzymes required for each conversion step in gastrin biosynthesis (fig1). In normal G cells, the enzymes responsible for production of carboxy terminal amidated gastrins mostly act in vesicles of the so called regulated pathway of exocytosis7; but these vesicles are scarce or absent in polyp and adenoma cells. As a consequence, these cells are poorly equipped both to store hormonal peptides and to complete the full sequence of events giving rise to carboxy amidated gastrins. Instead, peptides mostly corresponding to progastrin and Gly-gastrin are likely to pass directly from the Golgi complex to the cell surface by what is known as the constitutive route of secretion.
What regulates gastrin gene expression in colon polyps and adenomas? Studies by Nakata et al have shown that oncogenic Ras stimulates the mitogen activated protein kinase pathway and so increases gastrin gene expression.8 Recently, Kohet al demonstrated that the β-catenin/T cell factor 4 pathway also stimulates gastrin gene expression.9 Acquisition of mutations that activate the latter pathway is likely to be an early event in the progression to colorectal cancer and could account for the increased gastrin gene expression found by Smith and Watson. Whether or not similar mechanisms account for upregulation of the gastrin-CCKB receptor is not known.
Recently, Singh et al reported that mice with elevated plasma progastrin exhibit increased aberrant crypt foci, adenomas, and adenocarcinomas after treatment with azoxymethane.10 11 Aberrant crypt foci are considered to be a marker for progression to colon cancer. Singhet al suggest progastrin is a cocarcinogen, that is, on its own it is not carcinogenic but it increases the pool of transformed cells and so exacerbates the oncogenic progression. Interestingly, mice with elevated plasma concentrations of amidated gastrin did not exhibit increased aberrant crypt foci, adenomas, or carcinomas in response to azoxymethane. The picture emerges then that mutations acquired early in the progression to colorectal cancer lead to increased local production of progastrin and Gly-gastrin that then act as auto- or paracrine growth factors expanding the number of transformed cells. This analysis leaves open the role of the gastrin-CCKB receptor, and further work will certainly be needed on this point. Whether or not these findings can be developed into novel therapeutic strategies will depend on characterisation of the receptor mechanisms mediating the effects of progastrin or Gly-gastrin on colon epithelial proliferation.
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