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Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice
Author(s) -
Cobb Stephanie,
Wood Thomas,
Ceci Jeffrey,
Varro Andrea,
Velasco Marco,
Singh Pomila
Publication year - 2004
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.20094
Subject(s) - azoxymethane , aberrant crypt foci , genetically modified mouse , wild type , carcinogenesis , transgene , knockout mouse , colorectal cancer , carcinogen , mutant , medicine , adenoma , crypt , endocrinology , ratón , cancer research , biology , pathology , cancer , gene , receptor , biochemistry , colonic disease
BACKGROUND The authors recently reported that transgenic mice (h GAS ) expressing pharmacologic levels of progastrin (PG) (> 10 nM to 100 nM) exhibited increased susceptibility to colon carcinogenesis in response to azoxymethane (AOM). It is not known whether PG functions as a cocarcinogen at the concentrations observed in patients with hypergastrinemia (∼1.0 nM). METHODS The authors generated transgenic mice that overexpressed either wild‐type (wtPG) or mutant (mtPG) human PG in the intestinal mucosa using the murine fatty acid binding protein ( Fabp ) promoter. Fabp ‐PG mice and their wild‐type littermates were treated with AOM, and their colons were examined for preneoplastic (aberrant crypt foci [ACF]) and neoplastic (adenomas [Ads] and adenocarcinomas [AdCas]) lesions after 2 weeks and 6 months of treatment. RESULTS ACF and tumors were significantly more common (by a factor of ∼2) in colon specimens from both Fabp ‐wtPG mice and Fabp ‐mtPG mice relative to wild‐type mice. It is noteworthy that the multiplicity of ACF and the total number of small and large Ads and AdCas were significantly greater in colon specimens from Fabp ‐PG mice compared with colon specimens from wild‐type mice, irrespective of gender. CONCLUSIONS The results of the current study suggest that at concentrations (∼1.0 nM) far lower than the ones observed in h GAS mice, PG functions as an equally potent cocarcinogen and significantly increases the risk of colon carcinogenesis in response to AOM. Thus, PG may represent a clinically relevant target molecule in patients with hypergastrinemia or colon carcinoma. Cancer 2004. © 2004 American Cancer Society.