Gastrin, gastrin receptors and colorectal carcinoma

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Abstract
There is now abundant evidence that most colorectal carcinomas synthesise progastrin. Gastrin mRNA has been detected by both polymerase chain reaction and northern hybridisation in colorectal carcinoma cell lines, normal human colonic mucosa and colorectal carcinomas.6 16-18 The gastrin mRNA is of low abundance but the major band of 0.7 kilobases is identical in sequence to antral gastrin mRNA.6 16 17 There is, however, considerable disparity in the literature on the proportion of colorectal carcinomas that contain amidated gastrin (table 1). The variable efficiency of translation and extent of postranslational processing of gastrin in peptide producing tumours20 offers an explanation for some of the contradictory reports as assays for gastrin have frequently been confined to amidated forms. The processing of gastrin from progastrin to the amidated product involves a number of steps, which include endopeptidase and carboxypeptidase mediated cleavages, and which end in conversion of glycine extended gastrin to the amidated forms (fig1).21 22 Using either region specific antisera or processing independent analysis,20 which quantitates all molecular forms of gastrin irrespective of the degree of processing, progastrin or progastrin derived peptides are now being detected in 80–100% of colorectal carcinomas (table 1). The presence of non-amidated gastrin peptides in colorectal carcinomas has assumed greater importance with the recent reports that gastrin-gly has a growth promoting effect in a non-transformed colonic epithelial cell line,23 as well as in a pancreatic cancer cell line24 25 and in fibroblasts,26 and with the description of receptors capable of binding non-amidated gastrin.23 24 26 27 In addition, transgenic mice expressing human progastrin in the liver had raised concentrations of plasma progastrin and a hyperplastic colonic mucosa.28 The nature of the receptor responsible for the proliferative effects of progastrin is completely unknown.

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