Carcinogenesis Advance Access published online on March 2, 2006
Carcinogenesis, doi:10.1093/carcin/bgl003
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1 Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261; Lung and Thoracic Malignancy Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261
* To whom correspondence should be addressed. Several studies have suggested a possible role of the hepatocyte growth factor (HGF)/c-Met system in lung tumor development and progression. Extent of expression of both HGF and c-Met have been shown to be negative prognostic indicators of survival and recurrence in non-small cell lung cancer, especially adenocarcinoma. To further define a role for HGF in lung cancer development and growth, we have generated transgenic mice that overexpress HGF in the airway epithelium. HGF transgenic and wild-type mice were exposed to the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or saline control and sacrificed 10-38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. The HGF transgene was verified to be expressed only in the lungs of transgenic mice. The transgenic mouse lung histology exhibited congestion in the alveolar spaces, excess production of blood vessels and a convoluted pattern of airways with wide bifurcations. The number of lung tumors from NNK-treated transgenic animals versus the number of lung tumors from NNK-treated wild-type animals was significantly higher (P = 0.0001, Poisson regression). The percent of animals with tumors was 75% in the transgenic group compared to 48.8% in the wild-type group. The main effect was an increase in tumor multiplicity; average size of tumors was not different between the groups. Additionally, the tumors that arose in the transgenic mice contained increased HGF protein compared to tumors from the wild-type mice. These results indicate that lung carcinogenesis induced by a tobacco carcinogen is enhanced by expression of the HGF transgene. This model recapitulates the phenotype of aggressive lung adenocarcinoma that overexpress HGF and will be useful in evaluating anti-tumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.
Received November 9, 2005
Revised January 31, 2006
Accepted February 25, 2006
CANCER BIOLOGY
Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer
Laura P. Stabile 1,
Jennifer S. Lyker 2,
Stephanie R. Land 3,
Sanja Dacic 4,
Beth A. Zamboni 5,
and
Jill M. Siegfried 1 *
2 Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261
3 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261; Lung and Thoracic Malignancy Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261
4 Department of Pathology, Pittsburgh, PA 15261; Lung and Thoracic Malignancy Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261
5 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15261
Jill M. Siegfried, E-mail: siegfriedjm{at}upmc.edu
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