VEGF and PDGF in angiogenesis and tumor progression

VEGF 和 PDGF 在血管生成和肿瘤进展中的作用

• 批准号: 8052774
• 负责人: DAVID A CHERESH
• 金额: $ 46.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052774
• 关键词: Angiogenic Factor; Angiogenic Switch; Antineoplastic Agents; Binding; Biological; Blood Circulation; Blood Vessels; Cell Proliferation; Cell physiology; Complex; Development; Disease; Drug Delivery Systems; Endothelial Cells; Equilibrium; Goals; Growth; Growth Factor; Health; Imatinib; In Vitro; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Outcome; PDGFRA gene; PDGFRB gene; Pancreatic carcinoma; Patients; Perfusion; Pericytes; Physiological; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Primary Neoplasm; Process; Property; Recruitment Activity; Regulation; Role; Signal Transduction; Smooth Muscle Myocytes; Solid Neoplasm; Surface; System; Time; Tissues; Tumor Angiogenesis; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular remodeling; Wound Healing; angiogenesis; base; cell motility; design; improved; in vivo; inhibitor/antagonist; malignant state; neoplastic cell; neovascularization; new growth; novel therapeutics; platelet-derived growth factor BB; prevent; receptor; response; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：血管生成，即新血管从预先存在的血管生长，显著促进癌症进展和转移，因为“血管生成开关”代表实体瘤进展到更快生长和更恶性状态的基本步骤。与正常血管不同，肿瘤相关血管是众所周知的渗漏和曲折，导致其功能低下。因此，最近使肿瘤血管正常化的尝试已被证明是成功的，作为改善抗癌剂递送的手段。我们假设，通过使肿瘤血管系统正常化，应该可以通过限制肿瘤内渗来减少肿瘤细胞转移。在肿瘤血管生成过程中，血管内皮生长因子（VEGF）和其他血管生成生长因子刺激内皮细胞出芽并形成新血管。同时，由血小板衍生生长因子-BB（PDGF-BB）及其受体PDGFR 2刺激的血管平滑肌细胞被募集到肿瘤相关的血管芽，促进血管成熟。我们最近观察到VEGF的存在可以阻断PDGF依赖的新生血管形成和血管正常化的调节。因此，通过阻断VEGF或VEGF受体2，我们可以诱导增加肿瘤血管成熟。我们的假设是，VEGF通过其负调节周细胞上PDGFR 2功能的能力，不仅对原发性肿瘤的新血管形成和生长产生深远影响，而且还显着影响肿瘤细胞内渗，这是转移级联反应的初始步骤。我们提出的研究的一个主要目标是表征肿瘤血管相关周细胞上PDGFR 2/VEGFR 2复合物的组成，并研究其如何在体外调节细胞迁移和增殖（目的1）。我们将仔细研究VEGF抑制PDGF功能的机制，在小鼠血管生成过程中真实的时间内影响血管完整性和周细胞覆盖（目的2）。最后，我们将确定肿瘤细胞VEGF/PDGF的差异表达如何决定血管成熟和血管生成，并评估VEGF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（目的3）。基于这些研究，我们提出了一种新的治疗策略来控制肿瘤的进展和转移。公共卫生相关性：血管生成是新血管从现有血管系统发芽形成的过程。我们已经确定了一个令人惊讶的平衡之间的促血管生成因子，导致血管生成的封锁。为了设计新的治疗方法来操纵血管生成反应，以限制肿瘤生长，促进有效的药物递送，并最终改善患有转移性疾病的患者的结果，需要对该系统进行透彻的理解。