Normalization of tumor vasculature by R-Ras

R-Ras 使肿瘤血管正常化

基本信息

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
项目类别：
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

项目摘要

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）：由于长期的血管生成微环境，肿瘤中新形成的血管无法成熟为功能齐全的血管。这些血管的功能受损会阻碍药物输送，从而降低抗肿瘤治疗的功效。与肿瘤相关的过度血管通透性也使肿瘤细胞侵入循环系统，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。这项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 GTPase R-Ras 在肿瘤中建立成熟、功能性血管的重要作用。因此，R-Ras 促进肿瘤脉管系统的正常化。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标来控制肿瘤血管系统以获得治疗优势。 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 VEGFR2 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-周细胞关联，还通过 TGF-β 和 Jagged1 介导的 Notch 信号传导促进两种细胞类型之间的细胞间信号传导。这些途径促进内皮细胞静止和壁细胞分化；因此，它们对于血管的成熟很重要。基于这些观察，我们提出一个假设，即 R-Ras 协调这些途径，将新生肿瘤血管形成从血管生成发芽/分支过程重定向到成熟过程。在本提案中，我们将研究 R-Ras 通路在肿瘤血管化过程中的重要性和精确作用。在目标 1 中，我们将在使用各种培养/共培养系统的一系列体外实验中识别和表征介导 R-Ras 对内皮细胞和周细胞影响的关键信号通路。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。拟议的研究将为血管正常化现象的分子基础及其对肿瘤恶性肿瘤和治疗的影响提供重要的见解。