Role of endothelial cancer cell engulfment during metastatic brain invasion

内皮癌细胞吞噬在转移性脑侵袭过程中的作用

• 批准号: 8331470
• 负责人: Jaime Grutzendler
• 金额: $ 18.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-12 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331470
• 关键词: Actins; Animal Model; Area; Binding; Blood Vessels; Blood capillaries; Blood flow; Brain; Breast Cancer Cell; Cancer Patient; Caspase; Cell Death; Cells; Cerebrum; Cessation of life; Complex; Confocal Microscopy; Cytoskeleton; Data; Electron Microscopy; Embolism; Endothelial Cells; Endothelium; Enzymes; Epithelial Cells; Extravasation; Frequencies; Gelatinase A; Gelatinase B; Goals; Grant; Hypoxia; Image; Imaging Techniques; Individual; Infusion procedures; Inhibition of Matrix Metalloproteinases Pathway; Invaded; Knockout Mice; Lead; Life; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Membrane; Metastatic malignant neoplasm to brain; Methods; Microcirculation; Microscopy; Molecular; Monitor; Morbidity - disease rate; Mus; Mutant Strains Mice; Myosin ATPase; Myosin Light Chain Kinase; Neoplasm Metastasis; Outcome; Pathway interactions; Pharmacology; Play; Prevention; Preventive; Primary Brain Neoplasms; Process; Proliferation Marker; Relative (related person); Resolution; Role; Testing; Time; Transmission Electron Microscopy; Tumor Cell Invasion; Vascular Endothelial Growth Factors; base; cancer cell; capillary; cell killing; effective therapy; improved; in vivo; inhibitor/antagonist; killings; kinase inhibitor; malignant breast neoplasm; melanoma; metastatic process; mortality; neoplastic cell; neutralizing antibody; new therapeutic target; novel; prevent; research study; tissue fixing; two-photon

DESCRIPTION (provided by applicant): Brain metastases are a leading cause of mortality in cancer patients and there is currently no effective therapy that can prevent them. The search for therapies is limited by our poor understanding of the mechanisms of cancer cell brain invasion. We have recently discovered a novel mechanism of vascular plasticity that leads to the extravasation of emboli in the cerebral microcirculation. This process, which can clear any kind of material from the microvasculature, involves the engulfment of entire emboli by endothelial membrane projections and their subsequent translocation into the perivascular parenchyma. Our preliminary data shows that cancer cells undergo a similar process of microvascular engulfment. The goal of this proposal is to probe several potential roles of this mechanism in the metastatic process: a) cancer cells may co-opt this mechanism for the purpose of crossing the endothelial barrier and seeding the brain. This will be tested by using methods we have developed for transcranial two-photon imaging, confocal and electron microscopy. We will visualize at high spatial-temporal resolution the process of metastatic invasion in individual cerebral capillaries and determine if endothelial engulfment is required for cancer cell transvasation. b) the enveloping mechanism may help cancer cells remain insulated within microvessels promoting their latency. Using live and fixed tissue imaging and proliferation markers we will determine if cancer cells can remain dormant and viable for a long-term after microvessel engulfment. c) the engulfment process may serve as a surveillance mechanism by trapping and killing tumor cells within the vasculature. If the outcome of endothelial engulfment is death of malignant cells, we will monitor a variety of markers to characterize the death mechanism. Finally, we will examine several molecular pathways for their ability to modulate endothelial engulfment and will determine if this significantly impacts cancer cell transvasation, latency or survival. Together, these experiments will establish the importance of this mechanism of microvascular plasticity in the process of tumor invasion. Our results could suggest new targets for the prevention of brain metastasis.

描述（申请人提供）：脑转移是癌症患者死亡的主要原因，目前没有有效的治疗方法可以预防它们。由于我们对癌细胞侵入大脑的机制了解不足，对治疗方法的研究受到了限制。我们最近发现了一种导致脑微循环栓塞外渗的血管可塑性新机制。这个过程可以清除微血管中的任何物质，包括整个栓塞被内皮膜突起吞没，并随后转移到血管周围的实质。我们的初步数据表明，癌细胞经历了类似的微血管吞噬过程。本研究的目的是探讨这一机制在转移过程中的几个潜在作用：a)癌细胞可能利用这一机制穿越内皮屏障并进入大脑。这将通过使用我们开发的经颅双光子成像，共聚焦和电子显微镜的方法进行测试。我们将在高时空分辨率下观察单个脑毛细血管的转移性侵袭过程，并确定癌细胞横贯是否需要内皮吞噬。B)包膜机制可能有助于癌细胞在微血管内保持隔离，促进其潜伏期。使用活体和固定组织成像和增殖标记，我们将确定癌细胞在微血管吞噬后是否能长期保持休眠和存活。C)吞噬过程可以作为一种监视机制，通过在脉管系统内捕获和杀死肿瘤细胞。如果内皮吞噬的结果是恶性细胞的死亡，我们将监测各种标志物来表征死亡机制。最后，我们将研究几种分子途径调节内皮吞噬的能力，并确定这是否显著影响癌细胞的transvasation，潜伏期或存活。总之，这些实验将确立微血管可塑性机制在肿瘤侵袭过程中的重要性。我们的研究结果可能为预防脑转移提供新的靶点。