Intestinal Expression of Mutant and Wild-Type Progastrin Significantly Increases Colon Carcinogenesis in Response to Azoxymethane in Transgenic Mice

Stephanie Cobb, Thomas Wood, Jeffrey Ceci, Andrea Varro, Marco Velasco, Pomila Singh

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

BACKGROUND. The authors recently reported that transgenic mice (hGAS) 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 hGAS 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.

Original languageEnglish (US)
Pages (from-to)1311-1323
Number of pages13
JournalCancer
Volume100
Issue number6
DOIs
StatePublished - Mar 15 2004

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Azoxymethane
Transgenic Mice
Fatty Acid-Binding Proteins
Colon
Carcinogenesis
Aberrant Crypt Foci
Adenoma
Adenocarcinoma
Intestinal Mucosa
big gastrin
Carcinoma

Keywords

  • Aberrant crypt foci
  • Adenomas
  • Carcinomas
  • Colonic malignancy
  • Gastrins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Intestinal Expression of Mutant and Wild-Type Progastrin Significantly Increases Colon Carcinogenesis in Response to Azoxymethane in Transgenic Mice. / Cobb, Stephanie; Wood, Thomas; Ceci, Jeffrey; Varro, Andrea; Velasco, Marco; Singh, Pomila.

In: Cancer, Vol. 100, No. 6, 15.03.2004, p. 1311-1323.

Research output: Contribution to journalArticle

Cobb, Stephanie ; Wood, Thomas ; Ceci, Jeffrey ; Varro, Andrea ; Velasco, Marco ; Singh, Pomila. / Intestinal Expression of Mutant and Wild-Type Progastrin Significantly Increases Colon Carcinogenesis in Response to Azoxymethane in Transgenic Mice. In: Cancer. 2004 ; Vol. 100, No. 6. pp. 1311-1323.
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abstract = "BACKGROUND. The authors recently reported that transgenic mice (hGAS) 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 hGAS 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.",
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AU - Varro, Andrea

AU - Velasco, Marco

AU - Singh, Pomila

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N2 - BACKGROUND. The authors recently reported that transgenic mice (hGAS) 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 hGAS 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.

AB - BACKGROUND. The authors recently reported that transgenic mice (hGAS) 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 hGAS 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.

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