Nitric Oxide in Tumor Angiogenesis, Microcirculation and Radiation Therapy

描述（由申请人提供）：肿瘤血流的可重复性控制，这是向实体肿瘤最佳输送药物和氧气所必需的，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质。研究表明，由血管内皮NO合酶产生的NO可诱导血管生成，维持肿瘤血流。最近的研究结果表明，血管NO介导了血管周围细胞向血管生成血管的募集，以及血管的分支、纵向延伸和随后的稳定。然而，初步研究表明，肿瘤细胞和血管外基质细胞产生的NO可能与血管成熟过程相竞争。该项目的中心假设是NO在血管周围的选择性定位改善肿瘤血管形态和功能，改善药物和氧气的输送，从而改善伴随细胞毒性治疗的疗效。

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.