In the U.S., over 90% of lung cancers are detected in patients with tobacco-related and other chronic lung disorders. These disorders are characterized by alterations in the content and composition of the lung extracellular matrix. One matrix glycoprotein highly expressed in chronic lung disease is fibronectin (Fn), and we firmly believe that relative increases in the content of Fn in lung might promote lung carcinogenesis. Consistent with this idea, we have reported that Fn stimulates non small cell lung carcinoma (NSCLC) proliferation and reduces apoptosis suggesting that Fn may serve to promote tumor growth and survival. Further work revealed that these effects were related to increased expression of the pro-oncogene COX-2 and secretion of PGE2, a mitogen for lung carcinoma cells. More recently, we found that the stimulatory effect of Fn could be enhanced by its ability to induce the expression of EP4, a PGE2 receptor that mediates its mitogenic effects. Based on our preliminary data, we hypothesize that, in addition to inducing COX-2 expression and PGE2 biosynthesis, Fn binding to its integrin (5(1 receptor leads to activation of PI3-K/Akt/GSK-3 kinase signaling and induction of the transcription factor AP-2 which, in turn, leads to increased EP4 receptor expression thereby enhancing the mitogenic effect of PGE2 in tumor cells in vitro and in vivo. This hypothesis will be tested in the following specific aims.
Aim 1 : Explore the role of EP4 in Fn-induced lung carcinoma cell proliferation, and determine the cellular and molecular mechanism(s) by which Fn upregulates EP4 expression.
Aim 2 : Determine the role of Fn/(5(1 and EP4 receptors in experimental models of lung carcinogenesis using established model of lung carcinogenesis related to k-ras mutation and Lewis Lung Carcinoma (LLC) mouse models. This research program will be accompanied by comprehensive didactic sessions and strengthened by mentor/ collaborators and consultants that will enhance the investigator's skills and promote an independent career in academia.
