Spatial and Temporal Regulation of Angiogenesis

描述(申请人提供)：本PPG重点研究肿瘤血管生成、相关血管高通透性和间质生成的空间和时间调节。压倒一切的假设是，肿瘤血管和间质对肿瘤的生长和存活是必不可少的，它们为肿瘤治疗提供了有吸引力的靶点。我们的目标是更好地了解调节这些过程的促血管生成和抗血管生成的力量，以便找到新的攻击点，可以防止肿瘤血管生成和间质形成，并剥夺肿瘤现有的血管和间质。四个互动项目被提出：项目1将侧重于TR3/Nur77的作用，它是一个孤儿转录因子，在诱导血管生成和血管通透性方面起关键作用。还将阐明血管内皮生长因子-A调控Tr3/Nur77‘S表达和转录激活的信号通路。项目2将研究雷帕霉素对Akt-mTOR信号通路的影响，以及它对导致肿瘤生长抑制的肿瘤间质的影响。假设雷帕霉素抑制肿瘤血管生成比抑制肿瘤细胞更有效，这些抗间质作用在很大程度上介导了雷帕霉素的抗肿瘤效果。AIMS将寻求确定雷帕霉素的血管靶点，Akt-mTOR信号通路中介导其抗血管生成作用的分子变化，并探索Akt信号在肿瘤细胞跨血管内皮细胞转移中的作用。项目3将研究雌激素及其受体(ER？)的作用。血管生成和其他有利于全身血管生成和肿瘤生长的间质生成方面的研究。此外，它还将研究雌激素-ER？相互作用导致骨髓动员，在肿瘤部位聚集，并分化为支持肿瘤的肌成纤维细胞和组织细胞。项目4将调查凝血酶反应蛋白-1(TSP-1)的三个类型1重复(3TSR)成分与TRAIL受体激动剂抗体结合在抑制肿瘤生长方面的有效性。它还将确定介导TSP-1和3TSR抗血管生成活性的受体和信号分子。总之，这些临床前研究将有助于理解肿瘤诱导血管生成和间质形成的信号通路，并有望确定可用作癌症治疗靶点的途径和分子。

DESCRIPTION (provided by applicant): This PPG focuses on the spatial and temporal regulation of tumor angiogenesis, associated vascular hyperpermeability, and stroma generation. The overriding hypothesis is that tumor vessels and stroma are essential for tumor growth and survival and that they offer attractive targets for tumor therapy. The goal is to achieve a much better understanding of the pro- and anti-angiogenic forces that regulate these processes in order to find novel points of attack that can prevent tumor angiogenesis and stroma formation and deprive tumors of existing vessels and stroma. Four interactive Projects are proposed: Project 1 will focus on the role of TR3/Nur77, an orphan transcription factor critical for the induction of VEGF-A-induced angiogenesis and vascular permeability. It will also elucidate the signaling pathways by which VEGF-A regulates TR3/Nur77's expression and transcriptional activation. Project 2 will investigate the effects of rapamycin on the Akt-mTOR signaling pathway and its effects on tumor stroma that lead to tumor growth inhibition. The Hypothesis is that rapamycin inhibits tumor angiogenesis more potently than it inhibits tumor cells and that these anti-stromal effects mediate much of rapamycin's anti-tumor efficacy. Aims will seek to identify the vascular targets of rapamycin, the molecular changes in the Akt-mTOR signaling pathway that mediate its anti-angiogenic effects, and explore the role of Akt signaling on tumor cell trafficking across vascular endothelium. Project 3 will investigate the role of estrogen and its receptor (ER?) on angiogenesis and other aspects of stroma generation that favor systemic angiogenesis and tumor growth. Further, it will investigate the mechanisms by which estrogen-ER? interactions lead to bone marrow mobilization, accumulation in tumor sites, and differentiation into tumor-supporting myofibroblasts and histiocytes. Project 4 will investigate the effectiveness of the three type 1 repeats (3TSR) component of thrombospondin-1 (TSP-1), in combination with TRAIL receptor agonist antibodies, in inhibiting tumor growth. It will also identify the receptors and signaling molecules that mediate the anti-angiogenic activity of TSP-1 and 3TSR. Together these preclinical studies will contribute much to an understanding of the signaling pathways by which tumors induce angiogenesis and stroma formation and are expected to identify pathways and molecules that can be used as therapeutic targets in cancer treatment.