Lung cancer remains a devastating disease with the majority of patients developing distant metastasis. To identify genes that may regulate metastasis, we used representational differential analysis (RDA) to identify genes highly expressed in human lung carcinomas. RDA identified bone morphogenetic protein 2 (BMP-2) expression in lung cancer and subsequent studies showed BMP-2 is highly expressed in the majority of lung cancers with low levels of expression in normal lung tissue. We show that the inhibition of BMP-2 activity of the A549 lung cancer cell line injected into nude mice causes a significant decrease in tumor growth. We hypothesize that the mechanism(s) by which BMP-2 promotes the development of tumor growth occurs through stimulation of angiogenesis and production of growth promoting cytokines. We will test this hypothesis by performing the following studies. (1) To analyze BMP-2 regulation of angiogenesis, lung cancer cell lines will be co-injected into nude mice with Affi-blue agarose beads coated with albumin, recombinant BMP-2, or the BMP-2 antagonist, noggin. Differences in vessel cooption, regression, and proliferation will be assessed in developing tumors using immunohistochemistry. To determine the mechanism by which BMP-2 stimulates angiogenesis by assessing both the regulation of vascular endothelial growth factor (VEGF) and activation of BMP-2 specific receptors. Cell lines transfected with dominant negative BMP receptors will be used to determine which BMP receptor is activated to induce angiogenesis. (2) To examine the paracrine and autocrine regulation of BMP-2 on known growth promoting cytokines and assess the role of the identified cytokine in promoting bmp-2 stimulation of tumor growth and angiogenesis. (3) To examine in patient derived tissue samples whether the level of BMP-2 ligand and receptor expression in primary and metastatic lung tumors correlates with vascular invasion, tumor grade, cell differentiation, monocyte infiltration, and the frequency of distant metastatic spread. Our long-term goal is to use BMP-2 inhibiting therapy as a modality to prevent the progression of lung cancer.
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