Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM

Abstract

Recent studies show that nonamidated gastrins (Gly-gastrin and progastrin) stimulate colonic proliferation. However, the role of nonamidated vs. amidated gastrins in colon carcinogenesis has not been defined. We measured intermediate markers of carcinogenesis in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS) in response to azoxymethane (AOM). The hGAS mice showed significantly higher numbers of aberrant crypt foci (140-200% increase) compared with that in wild-type (WT) and INS-GAS mice (P < 0.05) after AOM treatment. The bromodeoxyuridine-labeling index of colonic crypts also was significantly elevated in hGAS mice vs. that in WT and INS-GAS mice. The results therefore provide evidence for a mitogenic and cocarcinogenic role of nonamidated gastrins (progastrin), which is apparently not shared by the amidated gastrins. Although nonamidated gastrins are now believed to mediate mitogenic effects via novel receptors, amidated gastrins mediate biological effects via different receptor subtypes, which may explain the difference in the cocarcinogenic potential of nonamidated vs. amidated gastrins. In conclusion, our results provide strong support for a cocarcinogenic role for nonamidated gastrins in colon carcinogenesis.

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

“…17,18,34 ACF are preneoplastic lesions that have the propensity to progress and become neoplastic if further DNA damage occurs; they are considered to be reliable intermediate markers for tumor development in mice and humans, 40,41 as was confirmed in our previous studies. 17,18 Mice were treated with AOM at the optimal concentration of 12 mg/kg body weight, which previously was reported to be effective in promoting preneoplastic and neoplastic changes in the colonic mucosae of FVB/N mice. 18 Groups of 6-week-old transgenic mice (5-10 mice per group) and their wild-type littermates received an IP injection of AOM once weekly for 3 weeks, as was reported previously.…”

“…17,18 Mice were treated with AOM at the optimal concentration of 12 mg/kg body weight, which previously was reported to be effective in promoting preneoplastic and neoplastic changes in the colonic mucosae of FVB/N mice. 18 Groups of 6-week-old transgenic mice (5-10 mice per group) and their wild-type littermates received an IP injection of AOM once weekly for 3 weeks, as was reported previously. 18 AOM injections were performed in a laminar flow hood within the biohazard facility at UTMB.…”

“…18 Groups of 6-week-old transgenic mice (5-10 mice per group) and their wild-type littermates received an IP injection of AOM once weekly for 3 weeks, as was reported previously. 18 AOM injections were performed in a laminar flow hood within the biohazard facility at UTMB. Control animals received saline alone.…”

“…We observed that in the presence of carcinogens, pharmacologic levels of circulating PG led to a significant increase in the proliferative index of colonic crypts; this increase resulted in significant increases in the number and multiplicity of aberrant crypt foci (ACF) and the number of neoplastic lesions (Ads and AdCas) observed in hGAS mice. 5,17,18 Similarly, treatment with G-Gly increased the risk of developing ACF in rats. 29 Under physiologic conditions, circulatory levels of the full-length precursor peptide PG typically are undetectably low.…”

COX-2 selective inhibition reverses the trophic properties of gastrin in colorectal cancer

“…Another biological property attributed to gastrin is its trophic effect on gastrointestinal (GI) mucosa, including its role in the pathogenesis of GI carcinogenesis (Koh et al, 1999;Stepan et al, 1999;Koh and Chen, 2000). Previous epidemiological studies have indicated that chronic hypergastrinaemia constitutes a risk factor for the development of colorectal cancer Sundler et al, 1986;Wolfe, 1992;Lamberts et al, 1999;Singh et al, 2000;Watson and Smith, 2001). Significant hypergastrinaemia occurs in association with a number of clinical conditions, including pernicious anaemia and Zollinger-Ellison syndrome and following the development of potent acid suppression in response to the administration of proton pump inhibitors (Klingensmith et al, 1999).…”