Normalization of tumor vasculature by R-Ras

描述（由申请人提供）：肿瘤最突出的特征之一是其异常血管系统。 在肿瘤环境中不断受到血管生成因子的刺激，新形成的血管不能发育成完全成熟和功能性的血管网络。 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，这种结构和功能异常的肿瘤脉管系统的正常化可以显著改善药物递送并增强常规细胞毒性疗法的功效。 因此，本研究的长期目标是了解肿瘤中病理再生血管系统成熟和正常化的分子机制。 我们最近的研究表明，一个小的GTdR，R-Ras，促进血管成熟，通过诱导内皮细胞的静止和促进形成基膜和周细胞鞘包裹新生血管。 在这个提议中，我们将确定R-Ras在体内调节肿瘤微血管成熟中的作用，分析体外这种调节的细胞机制，并使用R-Ras-null小鼠模型确定R-Ras介导的血管成熟在癌症中的治疗意义。 在目的1中，我们将研究R-Ras缺陷对体内肿瘤微血管结构和功能完整性的影响。 在目的2中，我们将进行R-Ras对与血管成熟过程相关的内皮细胞活性的影响的体外分析（例如粘附连接的形成和稳定以减少血管渗漏）。 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于两种细胞类型的分化和功能成熟至关重要。 在目标3中，我们将研究R-Ras如何通过促进肿瘤血管的成熟来影响肿瘤进展和细胞毒性治疗的治疗效果。 在这个目标中，我们还将确定是否正常化的肿瘤血管诱导的抗血管生成治疗和其临床效益与R-Ras在受影响的血管中的表达。 这些研究的结果可以为设计有效的癌症治疗方案提供依据。 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循环，阻碍了治疗剂向肿瘤的递送。 本申请提出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.