Elvis, der Gestaltwandler

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Gastrin and Gastrin Receptors in Colorectal Neoplasia

Colorectal cancer remains a common public health issue and a leading cause of mortality in the industrialised world. Much still needs to be learned about the factors regulating the proliferation of colonic epithelial cells but a large body of work suggests that the gastric antral hormone gastrin may be a trophic factor for colorectal cancer cells. This putative role for gastrin is controversial, however, and several questions remain unanswered. The aim of this thesis was to address several of these questions and investigate further the possible involvement of gastrin in colorectal neoplasia. In the first study (Chapter 9), the effects of omeprazole-induced endogenous hypergastrinaemia on the subsequent development of azoxymethane-induced colorectal neoplasia in rats was examined. Omeprazole was chosen because of the well documented elevations in circulating gastrin concentrations seen during therapy with this commonly prescribed drug. The azoxymethane model was chosen because of its similarities to human carcinogenesis and because it has been well characterised and widely used in recent years. Despite having marked hypergastrinaemia throughout the study, significantly fewer rats in the omeprazole group developed tumours and had fewer tumours per rat. The reasons for this are unclear but omeprazole is a potent inducer of the cytochrome P450 enzymes responsible for the metabolism of numerous carcinogens. It is possible that omeprazole treatment altered hepatic and/or intestinal azoxymethane metabolism, rendering it less effective as a colonic carcinogen. Future experiments are merited to investigate further the results of this study and these are discussed in Chapter 13. The second study (Chapter 10) examined the unresolved issue of whether plasma gastrin levels are elevated in colorectal tumour patients relative to patients without tumours. The study controlled for all known causes of hypergastrinaemia and measured both fasting and meal-stimulated plasma gastrin concentrations pre- and postoperatively. When studied in this manner, gastrin levels were similar in both tumour and control patients. In all but one case very high gastrins occurred in patients with positive gastric autoantibodies and were likely to result from undiagnosed atrophic gastritis or pernicious anaemia. Furthermore, no fall in gastrin concentrations was seen following presumed curative resection. It was notable that five tumour patients with perioperative loss of Helicobacter pylori (HP) infection had reductions in postoperative plasma gastrin. The results of previous studies should be reconsidered in the light of the important effects of HP infection on plasma gastrin. The results of this study have shown conclusively that colorectal tumour patients do not have higher circulating gastrin concentrations than well-matched controls. Next (Chapter 11), the content of gastrin and its processing-intermediates in samples of colonic carcinomas and disease-free mucosa was determined in a study aimed at assessing a possible role for gastrin as an autocrine growth factor in this malignancy. The study demonstrated the practical difficulties encountered in accurately measuring peptide levels in extracts of heterogeneous tissues. Once early technical problems of non-specific interference were resolved, the results showed that significant amounts of both bioactive, carboxyamidated gastrin and its processing-intermediates were present in both normal and malignant colon. Levels were similar in the two tissues although the results of trypsinisation suggest that tumours contain markedly more progastrin than corresponding normal mucosa. This is compatible with defective post- translational processing of gastrin in tumour cells although the lack of an antibody specific for progastrin itself prevents a definitive answer on this point. As peptide concentrations were similar in both tissues it is unlikely that synthesis of gastrin peptides is a novel feature restricted to neoplastic colorectal epithelium. It does not detract, however, from the hypothesis that gastrin produced locally may be a relevant trophic factor for tumour cells at this site. The final study (Chapter 12) explored further the possible presence of gastrin/CCK-B receptors in membranes preparations made from human colorectal cancers. The well characterised cell line AR42J was used as a 'positive control' to establish whether high affinity gastrin/CCK-B receptors could be detected by radioligand binding. This proved to be the case and no loss of binding was noted in crude membranes prepared from the cells. When a similar assay was applied to membranes from normal and malignant human colon, no convincing evidence for high affinity receptors was found although small amounts of specific binding of uncertain significance were observed. The possible reasons for the negative results are discussed as are alternative methods of studying these receptors. This issue is an important one to resolve before the increasing number of highly selective and potent gastrin/CCK-B receptor antagonists can be considered as possible therapeutic options for patients with colorectal cancer. In conclusion, the studies presented in this thesis have examined the role of gastrin in several ways

Oesophageal cell collection device and biomarker testing to identify high-risk Barrett’s patients requiring endoscopic investigation

The authors thank Professor Rebecca Fitzgerald for her expertise and advice in improving this manuscript. This work is presented on behalf of all members of the CytoSCOT group, including nursing and administrative staff, without whom this work would not have been possible.Peer reviewe