Rectal cell proliferation and colon cancer risk in patients with hypergastrinaemia

Abstract

Background-The influence of gastrin on the colonic mucosa is still uncertain. Some authors have suggested a stimulating eVect on the growth of normal and malignant colonic epithelium, while others have shown no association between gastrin and neoplastic development. Aims-To evaluate the eVect of gastrin on colorectal cell proliferation, patients with chronic endogenous hypergastrinaemia underwent proctoscopy. Biopsy specimens were taken in order to study rectal cell kinetics. Patients and controls-Ten patients with chronic autoimmune gastritis (CAG), six patients with Zollinger-Ellison syndrome (ZES), and 16 hospital controls took part in this study. Patients with CAG and ZES had basal serum gastrin concentrations significantly higher than controls (p<0.001). Methods-Immunohistochemistry was performed on 3 µm sections of rectal biopsy specimens incubated with 5'-bromodeoxyuridine. Results-The percentage of proliferating cells in the entire crypts (overall labelling index) was similar in all the groups. However, the labelling frequency in the upper two fifths of the glands (φh value) was significantly higher in patients with CAG or ZES compared with controls (p<0.01 in both patient groups versus controls). Conclusions-Endogenous hypergastrinaemia is associated with rectal cell proliferation defects, similar to those observed in conditions at high risk for colon cancer. The eVect of the increased serum concentrations of gastrin on the colorectal mucosa after treatment with drugs inhibiting gastric acid secretion should be investigated.

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

“…54 In certain disease states, such as Zollinger-Ellison syndrome, elevated plasma levels of nonamidated gastrins have been measured 30,31,55 ; these elevated levels may result in a predisposition toward colonic malignancy in a subpopulation of patients who also are positive for other associated risk factors. Hypergastrinemia reportedly is associated with mitogenic effects on colorectal mucosae 56,57 and with an increased risk of colonic malignancy 57,58 in a subpopulation of patients. Thus, there is good reason to believe that in patients with hypergastrinemia, circulating PG may play an important role in the initial stages of colon carcinogenesis.…”

Short term infusion of glycine-extended gastrin17 stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa

“…Studies of patients with classical causes of hypergastrinemia such as Zollinger-Ellison syndrome or pernicious anemia have suggested that, although colonic mucosal proliferative rates are increased, tumors do not occur more commonly. [37][38][39][40] The possibility should also be considered that immature gastrins rather than gastrin amide may be responsible for the hyperproliferative colonic mucosa in such hypergastrinemic states. 41,42 Although the available data is limited, serum concentrations of progastrin and glycine-extended intermediates are elevated in patients with Zollinger-Ellison syndrome, in greater proportion than gastrin amide.…”

Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation

“…The nonspecific gastrin inhibitors proglumide and benzotript, which appear to bind the 78-kDa potential receptor for the incompletely processed forms of gastrin (24), can inhibit the growth of colon cancer cell lines (25) as well as transplanted colon carcinomas (26). Patients with Zollinger-Ellison syndrome, which results in elevated levels of circulating amidated gastrin, G-Gly, and progastrin, also have increased colonic proliferation rates and a shift in the proliferative zone into the upper third of the crypt (27,28). Increased colonic proliferation and the expansion of the proliferative zone into the upper third of the crypt have been associated with an increased risk of developing colon cancer in humans (29,30).…”