Normalization of tumor vasculature by R-Ras

描述(申请人提供)：肿瘤最显著的特征之一是其异常的血管系统。在肿瘤环境中血管生成因子的不断刺激下，新形成的血管不能发育成一个完全成熟的、具有功能的血管网络。近年来，人们开始认识到肿瘤血管成熟不足和功能低下的生物学和临床意义。通过改善肿瘤内的循环，使这种结构和功能异常的肿瘤血管正常化可能会显著改善药物输送，并增强传统细胞毒治疗的疗效。因此，这项研究的长期目标是了解肿瘤中病理再生血管成熟和正常化的分子机制。我们最近的研究表明，一个小的GTP酶，R-RAS，通过诱导内皮细胞静止和促进包裹新生血管的周细胞鞘和基底膜的形成来促进血管成熟。在这个方案中，我们将在体内确定R-RAS在调节肿瘤微血管成熟中的作用，并在体外分析这种调节的细胞机制，并利用R-RAS缺失的小鼠模型来确定R-RAS介导的肿瘤血管成熟的治疗意义。目的1，探讨R-RAS缺乏对体内肿瘤微血管结构和功能完整性的影响。在目标2中，我们将在体外分析R-RAS对与血管成熟过程相关的内皮细胞活性的影响(例如，黏附连接的形成和稳定，以减少血管泄漏)。我们还将确定R-RAS在周细胞调节中的作用，包括在内皮-周细胞相互作用中的作用，因为这种相互作用对两种细胞的分化和功能成熟都是必不可少的。在目标3中，我们将研究R-RAS如何通过促进肿瘤血管成熟来影响肿瘤进展和细胞毒治疗的疗效。为此，我们还将确定抗血管生成治疗诱导的肿瘤血管正常化及其临床益处是否与受影响血管中R-RAS的表达有关。这些研究的发现可以为设计有效的癌症治疗方案提供理论基础。公共卫生相关性：肿瘤中血管发育异常。由于这种异常，恶性肿瘤缺乏足够的血液循环，阻碍了治疗药物的输送到肿瘤。这项应用旨在研究我们如何操纵肿瘤内的血管网络，以增强肿瘤对癌症化疗或放射治疗的反应。

DESCRIPTION (provided by applicant): One of the most prominent characteristics of tumors is their abnormal vasculature. Constantly stimulated by angiogenic factors in the tumor environment, newly formed blood vessels fail to develop into a fully mature and functional vascular network. In recent years, we have begun to recognize the biological and clinical significance of the deficiency in maturation and the poor functionality of tumor blood vessels. Through improvement of the circulation within the tumor, normalization of such structurally and functionally abnormal tumor vasculature may significantly improve drug delivery and enhance the efficacy of conventional cytotoxic therapies. The long term goal of this study is, therefore, to understand the molecular mechanism of maturation and normalization of pathologically regenerating vasculature in the tumor. Our recent studies suggest that a small GTPase, R-Ras, promotes vessel maturation through induction of endothelial quiescence and facilitation of the formation of basement membrane and the sheath of pericytes enwrapping the nascent vessels. In this proposal, we will determine the role of R-Ras in regulating the maturation of tumor microvessels in vivo, analyze the cellular mechanism of this regulation in vitro, and determine the therapeutic significance of R-Ras-mediated vessel maturation in cancer using an R-Ras-null mouse model. In Aim 1, we will investigate the effect of R-Ras deficiency on the structural and functional integrity of tumor microvessels in vivo. In Aim 2, we will conduct in vitro analysis of the effect of R-Ras on endothelial cell activities related to the vessel maturation process (e.g. formation and stabilization of adherent junction to reduce vessel leakiness). We will also determine the role of R-Ras in pericyte regulation, including the role in endothelial-pericyte interaction, as this interaction is essential for the differentiation and functional maturation of both cell types. In Aim 3, we will investigate how R-Ras affects the tumor progression and the therapeutic efficacies of cytotoxic treatments through promoting maturation of tumor vasculature. In this aim, we will also determine whether the normalization of tumor vasculature induced by antiangiogenic therapy and its clinical benefit are linked to the expression of R-Ras in the affected vessels. The findings from these studies could provide the rationale for design of effective cancer regimens. PUBLIC HEALTH RELEVANCE: Blood vessels develop abnormally in tumors. Due to this abnormality, malignant tumors lack adequate circulation, hindering the delivery of therapeutic agent to the tumors. This application proposes to investigate how we could manipulate the blood vessel network within the tumor in order to enhance tumor responses to chemotherapeutic or radiation treatments for cancer.