Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1547-1555 |
| Number of pages | 9 |
| Journal | Carcinogenesis |
| Volume | 27 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2006 |
Bibliographical note
Funding Information:This work was supported by a grant CA79882-04 awarded to J.M.S. from the National Cancer Institute. We would like to acknowledge Dr Susan Reynolds from the University of Pittsburgh for the CCSP antibody, Dr Brian Hackett for the p0GH plasmid, Dr Reza Zarnegar for the HGF cDNA and the University of Cincinnati Transgenic Mouse Facility for preparation of the transgenic mice. L.P.S. was supported by a Career Development Award from the Lung Cancer SPORE grant P50 CA9045440 awarded to J.M.S.
