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

Am J Physiol Gastrointest Liver Physiol. 2000 Mar;278(3):G390-9. doi: 10.1152/ajpgi.2000.278.3.G390.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Azoxymethane*
  • Bromodeoxyuridine
  • Carcinogens*
  • Colon / metabolism
  • Colonic Neoplasms / chemically induced*
  • Colonic Neoplasms / pathology
  • Disease Susceptibility
  • Gastrins / blood
  • Gastrins / genetics
  • Gastrins / metabolism*
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic / genetics
  • Precancerous Conditions / chemically induced*
  • Precancerous Conditions / pathology
  • Protein Precursors / blood
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*

Substances

  • Carcinogens
  • Gastrins
  • Protein Precursors
  • big gastrin
  • Bromodeoxyuridine
  • Azoxymethane