Activating mutations in the K-ras proto-oncogene occur in approximately 30% of lung adenocarcinomas, the most common subtype of non-small cell lung cancer (NSCLC). K-ras is a membrane-associated GTPase that activates multiple kinase pathways, several of which have transforming activity in cellular models. Which of these downstream mediators of K-ras contribute to lung tumorigenesis has not been fully elucidated. Moreover, no effective approaches are available for the treatment of K-ras-mutant NSCLC. Our global hypothesis is that oncogenic K-ras-induced lung tumorigenesis is driven in part by a host response to the presence of transformed alveolar epithelial cells. These cells arise from bronchioalveolar stem cells (BASCs) and secrete chemokines that recruit host inflammatory cells and endothelial cells, which, in turn, secrete chemokines and growth factors that promote lung tumorigenesis. We propose to test this hypothesis by the completion of two Specific Aims. The first Specific Aim is to examine whether CXCR2 loss in inflammatory cells is sufficient to inhibit lung tumorigenesis induced by oncogenic K-ras. We will achieve this by creating two new oncogenic K-ras-driven mouse models of lung cancer, one in which the chemokine receptor CXCR2 is depleted globally to confirm our finding that treatment of KrasLA1 mice with a CXCR2 neutralizing antibody blocks lung tumorigenesis, and the other in which CXCR2 is depleted specifically in inflammatory cells. We investigate whether lung tumorigenesis is abrogated in these mouse models. The second Specific Aim is to examine the mechanisms by which tumor/stromal cell interactions promote lung tumorigenesis in an in vitro co-culture model. We will examine whether lung stromal cells (fibroblasts, endothelial cells, and macrophages) affect lung tumor cells (BASCs and a lung adenocarcinoma cell line derived from KrasLA1 mice) in a bi-directional manner using well-defined endpoints for tumor cells (cell proliferation, migration, and invasion), BASCs (proliferation and differentiation), and stromal cells (cell proliferation, migration, and endothelial tube formation). We will investigate the role of CXCR2 in these bi-directional interactions, and we will identify novel chemokines and growth factors in the in vitro model by performing proteomic analysis on conditioned media samples. We hope to better understand the mechanisms by which tumor/stromal cell interactions promote lung tumorigenesis and to build a rationale to test CXCR2 as a target for lung cancer prevention and therapy.
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