Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.

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.

Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects.

Identifying new effective therapeutic treatments for lung cancer is critical to improving overall patient survival. We have targeted both the estrogen receptor (ER) and the epidermal growth factor receptor (EGFR) pathways using an ER antagonist, fulvestrant ("Faslodex"), and the selective EGFR tyrosine kinase inhibitor, gefitinib ("Iressa"), in non-small cell lung cancer (NSCLC) cells. Rapid activation of phospho-EGFR and phospho-p44/p42 mitogen-activated protein kinase by estrogen was observed, indicating nonnuclear ER transactivation of EGFR. Additionally, EGFR protein expression was down-regulated in response to estrogen and up-regulated in response to fulvestrant in vitro, suggesting that the EGFR pathway is activated when estrogen is depleted in NSCLC cells. Cell growth and apoptosis were examined in several NSCLC lines that express varying amounts of ERbeta, EGFR, and Neu but no full-length ERalpha. One cell line contained an EGFR mutation. Cells were exposed to 10 nmol/L estrogen and 10 ng/mL EGF and either 1 mumol/L fulvestrant or 1 mumol/L gefitinib alone or in combination. In all cell lines, the drug combination decreased cell proliferation up to 90% and increased apoptosis 2-fold. The relative responses to gefitinib and fulvestrant were similar regardless of ER and EGFR expression and mutation status. In an in vivo lung tumor xenograft model, the drug combination decreased tumor volume in severe combined immunodeficient mice by approximately 60% compared with 49% and 32% for gefitinib and fulvestrant treatment alone, respectively. Antitumor effects of the combination therapy were accompanied by biochemical and histologic evidence of increased apoptosis, decreased phospho-p44/p42 mitogen-activated protein kinase expression, and increased Ki-67 expression compared with individual treatment. These studies provide evidence of a functional interaction between the ER and the EGFR pathways in NSCLC.