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: 8096364
• 负责人: Jaime Grutzendler
• 金额: $ 21.61万
• 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/8096364
• 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. PUBLIC HEALTH RELEVANCE: Brain metastases are a leading cause of morbidity and mortality in cancer patients. Our limited understanding of the mechanism by which tumor cells enter the brain is hampering the search for preventive therapies. We have discovered a novel mechanism of microvascular plasticity that could have a critical role in the process of tumor cell brain invasion. This grant proposes to use animal models and imaging techniques that we have developed to test the importance of this mechanism in the process of tumor invasion and to probe the effect of its pharmacological inhibition on the progression of brain metastases.

描述（由申请人提供）：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。 由于我们对癌细胞脑侵袭机制的了解不足，对治疗方法的研究受到限制。 我们最近发现了一种新的机制，血管可塑性，导致脑微循环中的栓子外渗。 该过程可以从微血管系统清除任何种类的物质，涉及内皮膜突起对整个栓子的吞噬及其随后移位到血管周围实质中。 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。 该提议的目标是探索该机制在转移过程中的几个潜在作用：a）癌细胞可能为了穿过内皮屏障和接种脑的目的而吸收该机制。 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中转移性侵袭的过程，并确定内皮细胞吞噬是否是癌细胞渗透所必需的。B）包膜机制可以帮助癌细胞在微血管内保持绝缘，从而促进它们的潜伏期。 使用活的和固定的组织成像和增殖标记物，我们将确定癌细胞是否可以在微血管吞噬后长期保持休眠和存活。c）吞噬过程可以通过捕获和杀死脉管系统内的肿瘤细胞来充当监视机制。 如果内皮吞噬的结果是恶性细胞死亡，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细胞吞噬的能力，并确定这是否会显着影响癌细胞的渗透，潜伏期或生存。 总之，这些实验将确立这种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。 公共卫生相关性：脑转移是癌症患者发病率和死亡率的主要原因。 我们对肿瘤细胞进入大脑的机制的有限理解阻碍了预防性治疗的研究。 我们发现了一种新的微血管可塑性机制，可能在肿瘤细胞脑侵袭过程中发挥关键作用。 该基金建议使用我们开发的动物模型和成像技术来测试这种机制在肿瘤侵袭过程中的重要性，并探索其对脑转移进展的药理学抑制作用。