Normalization of tumor vasculature by R-Ras

R-Ras 使肿瘤血管正常化

• 批准号: 9283466
• 负责人: Masanobu Komatsu
• 金额: $ 13.06万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9283466
• 关键词: Actins; Address; Animal Model; Attention; Attenuated; Blood Circulation; Blood Vessels; CDH13 gene; Cell Differentiation process; Cerebral Edema; Chronic; Clinical; Coculture Techniques; Combined Modality Therapy; Drug Delivery Systems; Endothelial Cells; Extravasation; Funding; Genetic; Genetic Models; Goals; Impairment; In Vitro; Investigation; KDR gene; Knockout Mice; Link; Malignant Neoplasms; Mediating; Methods; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Mus; Neoplasm Metastasis; Oxygen; Pathway interactions; Pericytes; Permeability; Phosphorylation; Plasma; Process; Radiation therapy; Regulation; Role; Series; Signal Pathway; Signal Transduction; Structure; System; TGF-beta type I receptor; Therapeutic; Transforming Growth Factor beta; Transgenic Mice; Tumor Cell Invasion; Tumor Immunity; Tumor-Associated Process; Vascular Endothelial Growth Factors; Vascularization; base; blood perfusion; cadherin 5; cancer cell; cell motility; cell type; chemotherapeutic agent; clinically significant; experimental study; functional disability; gain of function; improved; in vivo; inducible gene expression; innovation; insight; nanomedicine; neoplastic cell; notch protein; public health relevance; response; targeted treatment; tumor; vascular abnormality

DESCRIPTION (provided by applicant): Newly formed blood vessels fail to mature into fully functional vessels in tumors due to the chronically angiogenic microenvironment. The functional impairment of these vessels hampers drug delivery, thereby diminishing the efficacy of antitumor therapies. Excessive vessel permeability associated with tumors also allows tumor cell invasion into the circulation facilitating metastatic spreading. Therefore, the ability to conrol vessel maturity in tumors provides a potential therapeutic opportunity. The long-term goal of this study is to understand the molecular basis for vascular maturation. Our recent studies uncovered an essential role of the small GTPase R-Ras in establishment of mature, functional blood vessels in tumors. Thus, R-Ras promotes normalization of the tumor vasculature. Now, the important new objective of this investigation is to determine the molecular pathway for R-Ras-mediated vessel regulation so that new molecular targets may be identified for controlling the tumor vasculature for therapeutic advantage. R-Ras enhances vascular integrity through regulation of VE-cadherin. Our recent studies also show that R-Ras attenuates VEGF signaling in endothelial cells by inhibiting VEGFR2 internalization upon VEGF stimulation. Furthermore, R-Ras not only promotes endothelial cell-pericyte association but also facilitates intercellular signaling between the two cell types via TGF-beta and Jagged1-mediated Notch signaling. These pathways promote endothelial cell quiescence and mural cell differentiation; therefore, they are important for vessel maturation. Based on these observations, we propose a hypothesis that R-Ras orchestrates these pathways to redirect nascent tumor vessel formation from an angiogenic sprouting/branching process to a maturation process. In this proposal, we will investigate the significance and precise roles of the R-Ras pathways during tumor vascularization. In Aim 1, we will identify and characterize the key signaling pathways mediating the R-Ras effects on endothelial cells and pericytes in a series of in vitro experiments using various culture/coculture systems. In Aim 2, we will validate the findings from Aim 1 in various animal models to determine the role of these mechanisms during the establishment of functional tumor vessels. The proposed studies will provide an important insight into the molecular basis for the vascular normalization phenomenon and its implications in tumor malignancy and therapies.

描述（由申请人提供）：由于慢性血管生成微环境，肿瘤中新形成的血管无法成熟为完全功能的血管。这些血管的功能损害阻碍药物递送，从而降低抗肿瘤疗法的功效。与肿瘤相关的过度血管渗透性也允许肿瘤细胞侵入循环，促进转移扩散。因此，控制肿瘤血管成熟的能力提供了潜在的治疗机会。本研究的长期目标是了解血管成熟的分子基础。我们最近的研究揭示了小GTCR-Ras在肿瘤中建立成熟的功能性血管中的重要作用。因此，R-Ras促进肿瘤血管系统的正常化。现在，这项研究的重要新目标是确定R-Ras介导的血管调节的分子途径，以便可以确定新的分子靶点，用于控制肿瘤血管系统的治疗优势。R-Ras通过调节VE-钙粘蛋白增强血管完整性。我们最近的研究还表明，R-Ras通过抑制VEGF刺激后的VEGFR 2内化来减弱内皮细胞中的VEGF信号传导。此外，R-Ras不仅促进内皮细胞-周细胞缔合，而且还通过TGF-β和Jagged 1介导的Notch信号转导促进两种细胞类型之间的细胞间信号转导。这些通路促进内皮细胞静止和壁细胞分化;因此，它们对血管成熟很重要。基于这些观察结果，我们提出了一个假设，R-Ras协调这些途径，重新定向新生肿瘤血管形成的血管生成萌芽/分支过程的成熟过程。在这个提议中，我们将研究R-Ras通路在肿瘤血管形成过程中的意义和确切作用。在目标1中，我们将确定和表征的关键信号通路介导的R-Ras的影响，在一系列的体外实验中，使用各种文化/共培养系统的内皮细胞和周细胞。在目标2中，我们将在各种动物模型中验证目标1的发现，以确定这些机制在功能性肿瘤血管建立过程中的作用。这些研究将为血管正常化现象的分子基础及其在肿瘤恶性和治疗中的意义提供重要的见解。