Liver kinase B1 in angiogenesis

项目总结 新近研究表明血管内皮细胞通过血管分泌因子促进肿瘤的发生 生长和转移。了解过量的血管分泌因子是如何 以及它们如何影响肿瘤的发展可能会揭开新的靶点 治疗。我们令人兴奋的初步数据显示，肝脏激酶B1(LKB1)是一种肿瘤 抑制基因，调节Neuropilin(NRP)-1和VEGF，提示LKB1可能 通过其抑制功能成为血管生成和肿瘤生长的中枢介质 NRP-1和血管内皮生长因子的表达。这个应用的中心假设是LKB1在两者中 内皮细胞和肿瘤细胞下调NRP-1和其他促血管生成因子(PDGF& FGFR)，同时抑制Sp1诱导的VEGF转录激活，从而维持 抑制血管生成和肿瘤生长的状态。有三个相互关联的目标 来证实或驳斥这一假设。目标1是确定LKB1是否会导致 通过抑制转录激活从而改变血管内皮生长因子的表达 生理性血管生成。目的2是确定LKB1是否抑制NRP-1和其他 非血管内皮生长因子介导的血管生成。最后，在目标3中，我们将确定 LKB1下调血管内皮细胞生长因子和NRP-1表达的作用 在活体内。我们完全期待这个项目的完成将有助于定义分子 LKB1抑制血管内皮生长因子转录表达和活性的机制 血管壁内的NRP-1和其他促血管生成因子(FGFR和PDGFR) 从而减少肿瘤生长和缺血性血管生成。

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.