VEGF and PDGF in angiogenesis and tumor progression

描述(申请人提供)：血管生成，即从先前存在的血管生长的新血管，对癌症的进展和转移有重要作用，因为“血管生成开关”代表了实体肿瘤向更快生长和更恶性状态发展的基本步骤。与正常血管不同，肿瘤相关血管是出了名的漏水和弯曲，导致它们的功能不佳。因此，最近使肿瘤血管正常化的尝试被证明是一种改善抗癌药物输送的方法。我们假设，通过使肿瘤血管正常化，应该有可能通过限制肿瘤内血管来减少肿瘤细胞的转移。在肿瘤血管生成过程中，血管内皮生长因子(VEGF)等血管生成因子刺激内皮细胞萌发，形成新血管。同时，在血小板衍生生长因子-BB(PDGF-BB)及其受体PDGFR2的刺激下，血管平滑肌细胞被招募到肿瘤相关的血管萌芽中，促进血管成熟。我们最近观察到，血管内皮生长因子的存在可以阻断PDGF对新生血管和血管正常化的依赖调节。因此，通过阻断血管内皮生长因子或血管内皮生长因子受体2，我们可以诱导更多的肿瘤血管成熟。我们认为，血管内皮生长因子通过对周细胞上PDGFR2功能的负性调节作用，不仅对原发肿瘤的新生血管和生长有深远的影响，而且显著影响肿瘤细胞内的血管生成，这是肿瘤转移级联反应的第一步。我们提出的研究的一个主要目标将是表征肿瘤血管相关周细胞上PDGFR2/VEGFR2复合体的组成，并研究它如何在体外调节细胞的迁移和增殖(目标1)。我们将在小鼠血管生成过程中实时仔细研究血管内皮生长因子抑制PDGF功能影响血管完整性和周细胞复盖率的机制(目标2)。最后，我们将确定肿瘤细胞中血管内皮生长因子/PDGF的差异表达如何决定血管成熟和血管生成，并评估血管内皮生长因子表达的调节如何影响小鼠原位和自发性胰腺癌的进展和转移特性(目标3)。基于这些研究，我们提出了一种控制肿瘤进展和转移的新的治疗策略。公共卫生相关性：血管生成是指通过从现有的血管系统中萌芽形成新的血管的过程。我们已经确定了导致阻断血管生成的促血管生成因子之间令人惊讶的平衡。为了设计新的治疗方法来控制血管生成反应，以限制肿瘤的生长，促进有效的药物输送，并最终改善转移性疾病患者的预后，需要对这一系统进行彻底的了解。

DESCRIPTION (provided by applicant): Angiogenesis, the growth of new blood vessels from pre-existing vessels, contributes significantly to cancer progression and metastasis, as the "angiogenic switch" represents a fundamental step in the progression of a solid tumor to a faster growing and more malignant state. Unlike normal vessels, tumor-associated blood vessels are notoriously leaky and tortuous, contributing to their poor function. Accordingly, recent attempts to normalize tumor blood vessels have proven successful as a means for improved delivery of anti-cancer agents. We hypothesize, that by normalizing the tumor vasculature, it should be possible to reduce tumor cell metastasis by limiting tumor intravasation. During tumor angiogenesis, vascular endothelial growth factor (VEGF) and other angiogenic growth factors stimulate endothelial cells to sprout and form new vessels. Simultaneously, vascular smooth muscle cells stimulated by platelet-derived growth factor-BB (PDGF-BB) and its receptor PDGFR2 are recruited to tumor associated vascular sprouts facilitating vessel maturation. We have recently made the observation that the presence of VEGF can block PDGF-dependent regulation of neovascularization and vessel normalization. Thus, by blocking VEGF or the VEGF receptor 2 we can induce increase tumor vessel maturation. It is our hypothesis that VEGF, through its capacity to negatively regulate PDGFR2 function on pericytes, not only has a profound influence on neovascularization and growth of primary tumors, but also significantly impacts tumor cell intravasation, an initial step in the metastatic cascade. A major goal of our proposed studies will be to characterize the composition of the PDGFR2/VEGFR2 complex on tumor vessel associated pericytes and investigate how it regulates the cell migration and proliferation in vitro (Aim 1). We will carefully examine the mechanism by which VEGF suppresses PDGF function impacting blood vessel integrity and pericyte coverage in real time during angiogenesis in mice (Aim 2). Finally, we will determine how differential expression of VEGF/PDGF by tumor cells determines vascular maturation and angiogenesis, and assess how regulation of VEGF expression impacts the progression and metastatic properties of orthotopic and spontaneous pancreatic cancer in mice (Aim 3). Based on these studies we propose a novel therapeutic strategy to control tumor progression and metastasis. PUBLIC HEALTH RELEVANCE: Angiogenesis is the process by which new blood vessels are formed by sprouting from the existing vasculature. We have identified a surprising balance between pro-angiogenic factors which results in the blockade of angiogenesis. A thorough understanding of this system is required for the design of new therapies to manipulate the angiogenic response in order to limit tumor growth, facilitate efficient drug delivery, and ultimately improve outcome for patients suffering from metastatic disease.