Mechanisms of tumor escape from anti-angiogenic therapy

肿瘤逃避抗血管生成治疗的机制

基本信息

批准号：
8693221
负责人：
Andrew Carl Dudley
金额：
$ 31.28万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8693221
关键词：
Ablation Acoustics Anastomosis - action Angiogenesis Inhibition Angiography Antibodies BRAF gene Binding Biological Assay Blocking Antibodies Blood Blood Vessels Blood capillaries Cell Line Cell-Cell Adhesion Cells Complex Confocal Microscopy Development Dyes Ear Employee Strikes Endothelial Cells Genetic Growth Human Immunohistochemistry Implant In Vitro Intercellular Junctions Life Link Liquid substance Manuscripts Maps Measures Mediating Melanoma Cell Migration Assay Modeling Molecular Mouse Cell Line Mus Neoplasms in Vascular Tissue Neural Crest PECAM1 gene Perfusion Play Population Refractory Role Solid Neoplasm Structure TFAP2A gene Tube Tumor Cell Line Tumor Escape Ultrasonics Vascular Cell Adhesion Molecule-1 Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascularization bevacizumab capillary cell motility cell type cellular imaging fluorophore in vivo intravital microscopy melanoblast melanocyte melanoma migration millimeter mimicry neoplastic cell neutralizing antibody novel overexpression prevent progenitor promoter public health relevance small hairpin RNA transcription factor tumor tumor growth two-photon

项目摘要

DESCRIPTION (provided by applicant): Solid tumors require new blood vessels to grow beyond a few cubic millimeters. Tumor blood vessels are complex and dysfunctional and multiple cell types may coalesce to form the tumor vasculature. In a striking example, some tumor cells may directly integrate within vascular structures or form tumor cell-lined conduits that carry blood and fluid (termed vascular mimicry, VM). We have recently isolated and characterized a novel subpopulation of vascular-like tumor cells identified by expression of the vascular cell adhesion molecule, CD31. These CD31+ tumor cells do not express VEGF receptors, they down-regulate the neural crest transcription factor/CD31 repressor AP-2alpha, and they form tumor blood vessels when engrafted in mice. Furthermore, CD31+ tumor cells do not respond to VEGF inhibition and are enriched in tumors challenged with VEGF neutralizing antibodies. In aim 1 we will use clonal populations of CD31- and CD31+ tumor cells we have derived from human and mouse cell lines and a spontaneous mouse melanoma model to determine the functional role of CD31 in forming perfused vascular structures in tumors. Aim 2 is to use cell ablation strategies and cutting-edge tumor perfusion studies to determine how CD31+ tumor cells mediate escape from anti-angiogenic therapy. In aim 3 we will define how loss of the neural crest specifer AP-2alpha controls CD31 expression and generates VM-competent tumor cells. For this aim, we will use genetic deletion and over- expression studies and intravital microscopy to visualize VM-competent tumor cells implanted in the mouse ear. Upon completion of our study aims, we will clarify how CD31+ tumor cells form functional connections with the host vasculature, the molecular mechanisms that generate and maintain this unique subpopulation, and how these vascular like tumor cells mediate escape from anti-angiogenic therapy.

描述（由申请人提供）：实体瘤需要新的血管生长以外的几立方毫米。肿瘤血管复杂且功能失调，多种细胞类型可能会结合形成肿瘤脉管系统。在一个惊人的例子中，一些肿瘤细胞可能直接整合在血管结构中，或形成携带血液和液体的肿瘤细胞衬管导管（称为血管模仿，VM）。我们最近分离并表征了通过表达血管细胞粘附分子CD31鉴定出的血管状肿瘤细胞的新型亚群。这些CD31+肿瘤细胞不表达VEGF受体，它们会下调神经Crest转录因子/CD31阻遏物AP-2Alpha，当植入小鼠中时，它们会形成肿瘤血管。此外，CD31+肿瘤细胞对VEGF抑制作用无反应，并且富含受VEGF中和抗体挑战的肿瘤。在AIM 1中，我们将使用CD31和CD31+肿瘤细胞的克隆种群，我们源自人和小鼠细胞系以及自发小鼠黑色素瘤模型来确定CD31在形成灌注肿瘤中灌注血管结构中的功能作用。 AIM 2是使用细胞消融策略和尖端的肿瘤灌注研究来确定CD31+肿瘤细胞如何介导抗血管生成疗法的逃脱。在AIM 3中，我们将定义神经Crest Specifer AP-2Alpha的丢失如何控制CD31的表达并产生VM能力的肿瘤细胞。为此，我们将使用遗传缺失和过度表达研究和插入式显微镜来可视化植入小鼠耳朵中的VM能吸收的肿瘤细胞。研究完成后，我们将阐明CD31+肿瘤细胞与宿主脉管系统的功能连接，产生和维持这种独特亚群的分子机制以及这些像肿瘤细胞这样的血管细胞如何介导抗血管生成治疗。