Carcinogenesis Advance Access originally published online on March 2, 2006
Carcinogenesis 2006 27(8):1547-1555; doi:10.1093/carcin/bgl003
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Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer
1 Department of Pharmacology Pittsburgh, PA 15261, USA
2 Department of Biostatistics, University of Pittsburgh Pittsburgh, PA 15261, USA
3 Department of Pathology Pittsburgh, PA 15261, USA
4 Lung and Thoracic Malignancy Program, University of Pittsburgh Cancer Institute Pittsburgh, PA 15261, USA
*To whom correspondence should be addressed at: The Hillman Cancer Center, UPCI Research Pavilion, Suite 2.18, 5117 Centre Avenue, Pittsburgh, PA 15213-1863, USA. Tel: +1 412 623 7769; Fax: +1 412 623 7768; Email: siegfriedjm{at}upmc.edu
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 killed 10–38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. It was verified that the HGF transgene was 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 percentage of animals with tumors was 75% in the transgenic group compared with 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 with 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 overexpresses HGF and will be useful in evaluating antitumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.
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