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）：实体瘤需要新血管生长超过几立方毫米。肿瘤血管复杂且功能失调，多种细胞类型可能结合形成肿瘤脉管系统。在一个引人注目的例子中，一些肿瘤细胞可能直接整合到血管结构内或形成携带血液和液体的肿瘤细胞排列的导管（称为血管拟态，VM）。我们最近分离并表征了一种新的血管样肿瘤细胞亚群，通过血管细胞粘附分子 CD31 的表达进行鉴定。这些 CD31+ 肿瘤细胞不表达 VEGF 受体，它们下调神经嵴转录因子/CD31 阻遏物 AP-2α，并且在移植到小鼠体内时形成肿瘤血管。此外，CD31+肿瘤细胞对VEGF抑制没有反应，并且在用VEGF中和抗体攻击的肿瘤中富集。在目标 1 中，我们将使用源自人类和小鼠细胞系的 CD31- 和 CD31+ 肿瘤细胞克隆群以及自发性小鼠黑色素瘤模型来确定 CD31 在形成肿瘤中灌注血管结构中的功能作用。目标 2 是利用细胞消融策略和尖端肿瘤灌注研究来确定 CD31+ 肿瘤细胞如何介导逃避抗血管生成治疗。在目标 3 中，我们将定义神经嵴特异性 AP-2alpha 的缺失如何控制 CD31 表达并产生具有 VM 能力的肿瘤细胞。为此，我们将使用基因缺失和过度表达研究以及活体显微镜来观察植入小鼠耳中的具有 VM 能力的肿瘤细胞。完成我们的研究目标后，我们将阐明 CD31+ 肿瘤细胞如何与宿主脉管系统形成功能连接、产生和维持这一独特亚群的分子机制，以及这些血管样肿瘤细胞如何介导逃避抗血管生成治疗。