Liver kinase B1 in angiogenesis

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PROJECT SUMMARY Recent evidence indicates that endothelial cell via angiocrine factors promote tumor growth and metastasis. Understanding how excessive amount of angiocrine factors are produced and how they influence tumor development might unveil novel targets for therapies. Our exciting preliminary data demonstrates Liver Kinase B1 (LKB1), a tumor suppressor gene, regulates Neuropilin (NRP)-1 and VEGF, suggesting that LKB1 may be a central mediator of angiogenesis and tumor growth through its inhibitory function on NRP-1 and VEGF. The central hypothesis of this application is that LKB1 in both ECs and tumor cells down-regulates NRP-1 and other pro-angiogenic factors (PDGF & FGFR) while inhibiting Sp1-induced VEGF transcriptional activation thereby maintaining a state of suppressed angiogenesis and tumor growth. There are three interrelated aims to validate or to refute this hypothesis. Aim 1 is to establish if LKB1 leads to decreased VEGF expression through impeding transcriptional activation hence altering physiological angiogenesis. Aim 2 is to establish if LKB1 suppresses NRP-1 and other non-VEGF growth factors-mediated angiogenesis. Finally, in Aim 3, we will determine the contribution of LKB1 down-regulation of VEGF and NRP-1 within the vascular niche in vivo. We fully anticipate the completion of this project will help define the molecular mechanism by which LKB1 suppresses transcriptional expression and activity of VEGF, NRP-1, and other pro-angiogenic factors (FGFR & PDGFR) within the vascular niche resulting in a reduction in tumor growth and ischemic angiogenesis.