Normalization of tumor vasculature by R-Ras

R-Ras 使肿瘤血管正常化

• 批准号: 7843732
• 负责人: Masanobu Komatsu
• 金额: $ 39.63万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843732
• 关键词: Adult; Affect; Angiogenesis Inhibitors; Angiogenic Factor; Basement membrane; Biological; Blood Circulation; Blood Vessels; Breast Carcinoma; Cell Death; Cells; Characteristics; Clinical; Collagen Type IV; Combined Modality Therapy; Cytotoxic Chemotherapy; Drug Delivery Systems; Endothelial Cells; Endothelium; Environment; Goals; Hemangioma; Human; Hyperplasia; In Vitro; Ionizing radiation; Knockout Mice; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mitogens; Mitotic; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Natural regeneration; Neoplasms in Vascular Tissue; Oncogene Proteins; Pericytes; Pharmaceutical Preparations; Process; Property; Proteins; Radiation; Radiation therapy; Regimen; Regulation; Resistance; Role; Smooth Muscle Myocytes; Testing; Therapeutic; Therapeutic Agents; Thick; Tissues; Treatment Efficacy; Tumor Angiogenesis; Tumor Oxygenation; Tumor-Associated Process; Vascular Endothelial Cell; adherent junction; base; cancer cell; cancer therapy; cell type; chemotherapeutic agent; clinically significant; cytotoxic; design; improved; in vivo; insight; irradiation; mouse model; novel; public health relevance; response; tumor; tumor growth; tumor progression

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.

描述（由申请人提供）：肿瘤最突出的特征之一是它们的异常脉管系统。 在肿瘤环境中，新形成的血管不断受到血管生成因素的刺激，无法发展为完全成熟和功能性的血管网络。 近年来，我们已经开始认识到成熟缺乏和肿瘤血管功能不佳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归一化可能会显着改善药物递送并提高常规细胞毒性疗法的疗效。 因此，这项研究的长期目标是了解肿瘤中病理再生脉管系统的成熟和归一化的分子机制。 我们最近的研究表明，一个小的GTPase R-RAS通过诱导内皮静止和促进地下膜形成和周细胞鞘的形成来促进血管的成熟。 在该建议中，我们将确定R-RAS在体内调节肿瘤微血管成熟中的作用，分析体外调节的细胞机制，并使用R-RAS-NULL小鼠模型确定RAS介导的血管成熟的治疗意义。 在AIM 1中，我们将研究R-RAS缺乏对体内肿瘤微血管的结构和功能完整性的影响。 在AIM 2中，我们将在体外分析R-RAS对与血管成熟过程有关的内皮细胞活性的影响（例如，粘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 - 周期性相互作用中的作用，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AIM 3中，我们将研究R-RAS如何通过促进肿瘤脉管系统的成熟来影响细胞毒性治疗的肿瘤进展和治疗效率。 在此目标中，我们还将确定抗血管生成疗法诱导的肿瘤脉管系统的归一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癌症方案的设计提供理由。 公共卫生相关性：血管在肿瘤中异常发育。 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。 该应用建议调查如何操纵肿瘤内的血管网络，以增强肿瘤对癌症化学治疗或放射治疗的反应。