Increased susceptibility to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in transgenic mice overexpressing c-myc and epidermal growth factor in alveolar type II cells

J Cancer Res Clin Oncol. 2003 Feb;129(2):71-5. doi: 10.1007/s00432-002-0400-z. Epub 2003 Feb 19.

Abstract

Purpose: As previously described, SPC/myc transgenic mice developed bronchioloalveolar adenocarcinomas derived from alveolar type II (AT II) cells within 10-14 months, whereas SPC/IgEGF transgenic mice developed hyperplasias. Our purpose was to determine the potential interplay of environmental and genetic factors in lung tumorigenesis.

Materials and methods: Six-week-old SPC/myc and SPC/IgEGF transgenic mice, overexpressing c-myc and a secretable form of the epidermal growth factor (IgEGF) under the control of the surfactant protein C (SPC) promoter, were treated with a single dose of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). As control groups, SPC/myc and SPC/IgEGF transgenic mice were treated with NaCl and non-transgenic littermates were treated with NNK or NaCl, respectively.

Results: After 6 months, none of the NaCl-treated transgenic littermates showed bronchioloalveolar hyperplasia and adenocarcinoma formation, whereas 100% of the NNK-treated SPC/myc transgenic mice did. The effect of NNK on SPC/IgEGF transgenic mice was less pronounced, inducing hyperplasia in the lung in only 16.7% of them. In 90% of the NNK-treated non-transgenic littermates no neoplastic changes were detected in the lung.

Conclusions: These results demonstrate that the progression of pulmonary bronchioloalveolar adenocarcinomas, induced by expression of c-myc as a transgene, was accelerated by NNK, suggesting that c-myc cooperates with NNK-induced mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Bronchiolo-Alveolar / chemically induced
  • Adenocarcinoma, Bronchiolo-Alveolar / etiology*
  • Adenocarcinoma, Bronchiolo-Alveolar / genetics
  • Adenocarcinoma, Bronchiolo-Alveolar / pathology
  • Animals
  • Carcinogens / adverse effects*
  • Epidermal Growth Factor / genetics*
  • Gene Expression Regulation, Neoplastic
  • Hyperplasia / chemically induced
  • Intercellular Signaling Peptides and Proteins
  • Lung / drug effects*
  • Lung / pathology
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Transgenic
  • Nitrosamines / adverse effects*
  • Peptides / genetics*
  • Proto-Oncogene Proteins c-myc / genetics*
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactants

Substances

  • Carcinogens
  • Intercellular Signaling Peptides and Proteins
  • Nitrosamines
  • Peptides
  • Proto-Oncogene Proteins c-myc
  • Pulmonary Surfactant-Associated Protein C
  • Pulmonary Surfactants
  • Sftpc protein, mouse
  • Epidermal Growth Factor
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone