Mucin-depleted foci show strong activation of inflammatory markers in 1,2-dimethylhydrazine-induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

Int J Cancer. 2009 Aug 1;125(3):541-7. doi: 10.1002/ijc.24417.

Abstract

Mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucins, have been identified in the colon of carcinogen-treated rodents and in humans at high risk for colon cancer. The lack of the protective layer of mucus may cause inflammation which has been linked to colon carcinogenesis, therefore, the expression of markers such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS) and macrophage infiltration was studied with immunohistochemistry (IH) in MDF harvested from F344 rats treated with the colon carcinogen 1,2-dimethylhydrazine (DMH). The same determinations were performed in aberrant crypt foci (ACF) and, at a later time point, in tumours. A dramatic increase in COX-2, i-NOS and macrophage infiltration was observed in MDF but ACF showed a moderate increase compared with the paired normal mucosa. Tumours were positive for all the markers. RT-PCR experiments demonstrated that i-NOS RNA expression was increased in a set of MDF confirming the results obtained with immunohistochemistry. In an inflammation-cancer experimental model [mice treated with azoxymethane (AOM) and dextran sodium sulphate (DSS)], we observed that DSS-induced inflammation promoted MDF in a dose-dependent manner, whereas ACF were not affected. In conclusion, we report here for the first time a strong activation of the inflammatory process in MDF, which may contribute to the further progression of MDF to tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dimethylhydrazine
  • Animals
  • Azoxymethane
  • Carcinogens
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / metabolism*
  • Colitis / chemically induced
  • Colitis / complications*
  • Colitis / metabolism
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Dextran Sulfate / adverse effects*
  • Disease Models, Animal
  • Down-Regulation
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Immunohistochemistry
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Male
  • Mucin-2 / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Precancerous Conditions / chemically induced
  • Precancerous Conditions / enzymology
  • Precancerous Conditions / metabolism*
  • Precancerous Conditions / pathology
  • Rats
  • Rats, Inbred F344
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation

Substances

  • Carcinogens
  • Muc2 protein, rat
  • Mucin-2
  • Dextran Sulfate
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • 1,2-Dimethylhydrazine
  • Azoxymethane