Nitric Oxide in Tumor Angiogenesis, Microcirculation and Radiation Therapy

一氧化氮在肿瘤血管生成、微循环和放射治疗中的作用

基本信息

批准号：
7618192
负责人：
Dai Fukumura
金额：
$ 31.08万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7618192
关键词：
Address Angiogenic Factor Angiopoietin-1 Area Blood Vessels Blood flow Breast Cancer Model Caliber Cell Communication Cell Maturation Cell Proliferation Cells Combined Modality Therapy Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cytotoxic Chemotherapy Development Dominant-Negative Mutation Drug Delivery Systems Endothelial Cells Fluorescence Genes Genetic Glioma Goals Grant Histology Immunohistochemistry In Vitro Liposomes Mammary Neoplasms Measures Mediating Mediator of activation protein Methods Microcirculation Migration Assay Modeling Modification Molecular Monitor Morphology Mus Neoplasms in Vascular Tissue Nitric Oxide Nitric Oxide Donors Nitric Oxide Synthase Oxygen Pathologic Processes Pathway interactions Pattern Penetration Pericytes Perivascular Neoplasm Permeability Pharmaceutical Preparations Physiological Play Process Production Protein Isoforms Radiation Radiation Tolerance Radiation therapy Receptor Signaling Recombinants Reporter Reporting Resolution Role SKIL gene Sepharose Signal Pathway Signal Transduction Solid Neoplasm Soluble Guanylate Cyclase Source Stromal Cells Structure TIE-2 Receptor Techniques Testing Tissue Engineering Transgenic Mice Tumor Angiogenesis Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis cell motility density design functional improvement human NOS3 protein improved in vivo inhibitor/antagonist intravital microscopy knock-down migration neoplastic cell novel novel strategies overexpression response small hairpin RNA tissue oxygenation tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): The reproducible control of tumor blood flow, which is required for the optimal delivery of drugs and oxygen to solid tumors, remains an elusive goal. Nitric oxide (NO) is a multifunctional mediator of an array of physiological and pathological processes. It has been shown that NO derived from vascular endothelial NO synthase induces angiogenesis and maintains tumor blood flow. Recent results show that vascular NO mediates the recruitment of perivascular cells to angiogenic vessels, as well as the branching, longitudinal extension and subsequent stabilization of the vessels. However, preliminary studies suggest that NO produced by tumor and stromal cells outside the vascular area may compete with the process of vessel maturation. The central hypothesis of this project is that selective localization of NO around blood vessels improves tumor vascular morphology and function, the delivery of drugs and oxygen, and thus the efficacy of concomitant cytotoxic therapy. Orthotopic glioma and breast tumors grown in transparent window models in mice will be studied. In Aim 1, non-vascular sources of NO production will be blocked and vascular NO will be increased by means of genetic and pharmacological modifications. The effect of these modifications on tumor vascular function and tissue oxygenation will be determined by high-resolution intravital microscopy techniques and immunohistochemistry. Perivascular cells will be monitored in vivo using fluorescence-reporter transgenic mice. Finally, the tumor response to fractionated radiation during NO modifications will be determined. The angiopoietin (Ang)-Tie2 pathway has been shown to mediate vessel maturation via perivascular cell recruitment. In Aim 2, involvement of vascular NO in Ang-Tie2-induced perivascular cell recruitment as well as in downstream signaling of NO-dependent perivascular cell recruitment will be determined using recently established in vitro migration assays and a tissue-engineered blood vessel model as well as tumor models. Recent results show that blockade of vascular endothelial growth factor receptor 2 (VEGFR2) transiently improves perivascular cell coverage, tissue oxygenation and response to radiation therapy in tumors via Tie2 receptor signaling. In Aim 3, the role of vascular NO in anti-VEGFR2 treatment-induced vascular effects and the impact of vessel-selective localization of NO on the efficacy of combined anti-VEGFR2 and radiation treatments will be determined using the models and methods of Aim 1. In support of the central hypothesis, preliminary studies show that elimination of non-vascular sources of NO improves the structure and function of tumor vessels and enhances tumor response to fractionated radiation therapy. This project will advance the basic understanding of NO-mediated vessel maturation and help develop novel strategies to improve the delivery of drugs and oxygen to tumors.

描述（由申请人提供）：对肿瘤血流的可重复控制，这是最佳递送药物和氧气向实体瘤所必需的，仍然是一个难以捉摸的目标。一氧化氮（NO）是一系列生理和病理过程的多功能介体。已经显示，没有源自血管内皮的NO合酶诱导血管生成并保持肿瘤血流。最近的结果表明，血管NO介导血管周围细胞募集到血管生成血管，以及分支，纵向延伸和随后的血管稳定。然而，初步研究表明，血管区域以外的肿瘤和基质细胞不会与血管成熟过程竞争。该项目的中心假设是，NO周围血管的选择性定位可改善肿瘤血管形态和功能，药物和氧气的递送，从而改善伴随细胞毒性疗法的功效。将研究小鼠透明窗户模型中生长的原位神经胶质瘤和乳腺肿瘤。在AIM 1中，无生产的非血管来源将被阻止，而血管NO将通过遗传和药理修饰增加。这些修饰对肿瘤血管功能和组织氧合的影响将由高分辨率内置显微镜技术和免疫组织化学确定。血管周细胞将在体内使用荧光 - 重生蛋白转基因小鼠进行监测。最后，将确定无修饰过程中对分离辐射的肿瘤反应。血管生成素（ANG）-TIE2途径已显示通过血管周细胞募集介导血管成熟。在AIM 2中，使用最近建立的体外迁移测定法和组织工程的血管模型，将确定血管NO在ANG2诱导的周围诱导的血管周围细胞募集以及NO依赖性周围血管周围细胞募集的下游信号传导中的参与以及作为肿瘤模型。最近的结果表明，通过TIE2受体信号传导，血管内皮生长受体2（VEGFR2）的阻断会暂时改善血管周细胞覆盖率，组织氧合和对肿瘤放射治疗的反应。在AIM 3中，使用AIM 1的模型和方法，将确定血管NO在抗VEGFR2治疗诱导的血管效应以及NO对组合抗VEGFR2和放射治疗功效的船舶选择性定位的影响以及AIM的模型和方法1的影响。。为了支持中心假设，初步研究表明，消除非血管源的NO可以改善肿瘤血管的结构和功能，并增强肿瘤对分离放射治疗的反应。该项目将提高对无介导的血管成熟的基本理解，并有助于制定新的策略，以改善药物和氧气向肿瘤的递送。