Defining the First Hours of Lung metastasis using Intravital Live-Imaging

使用活体实时成像定义肺转移的最初几个小时

• 批准号: 8464682
• 负责人: MATTHEW F KRUMMEL
• 金额: $ 15.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464682
• 关键词: Accounting; Address; Air; Area; Behavior; Bone Marrow; Cell Communication; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Complex; Coupled; Deltastab; Development; Disease; Distal; Environment; Environmental air flow; Excision; Face; Goals; Grant; Hour; Human; Image; Imagery; Immune; Immune system; Immunologic Surveillance; Immunology; Individual; Interleukin-4; Investigation; Kinetics; Knowledge; Label; Lead; Life; Liquid substance; Liver; Lung; Malignant Neoplasms; Metastatic Neoplasm to the Lung; Methodology; Methods; Mus; National Institute of Allergy and Infectious Disease; Nature; Neoplasm Metastasis; Organ; Pathway interactions; Physiological; Population; Primary Neoplasm; Process; Proteins; Recruitment Activity; Relative (related person); Resolution; Risk; Role; Site; Skin; Specificity; Structure of parenchyma of lung; Techniques; Testing; Time; Tissues; base; cell motility; cell type; in vivo; innovation; intravital imaging; intravital microscopy; macrophage; multi-photon; neoplastic cell; novel; repaired; response; spatiotemporal; success; tumor

DESCRIPTION (provided by applicant): It is believed that the lung is a permissive organ for the seeding of certain metastasizing tumors. Recent studies have supported this, finding that distal primary tumors instigate bone marrow-derived cell (BMDC) migration into the lung, forming a pre-metastatic niche (PreMN), and that these cells are crucial for robust and efficient metastasis. These studies have led to a growing recognition of the importance of the immune system and the pulmonary PreMN in lung metastasis, but many important questions remain and have been hitherto inaccessible. Most notably, there has been no direct way of assessing the behavior and fate of DTCs within the lung PreMN versus normal 'less-permissive' lung tissue. Further, the PreMN contains a diverse set of immune cells and the effect of interaction with these populations on DTC survival is unknown. In order to understand and therapeutically target pulmonary metastasis we must first address these crucial questions, in vivo The basis for this R21 exploratory grant is to apply novel real-time intravital imaging approaches to understand how the lung deals with incoming cells. Of particular relevance are to understand why and how metastatic cells survive in the environment and how host-cells 'receive' them and protect them from normal elimination of cells from the vasculature. We hypothesize that normal removal of cells from microvasculature is a repair process which metastatic cells, helped by host cells, extend in duration to achieve successful colonization. The overall success of this project will be defined by our knowledge of the spatiotemporal landscape that metastatic cells face upon their arrival in the lung. Are tumor cells seeded followed by being joined by 'helper' host cells or are successful mets captured directly by these cells? What are the kinetics of the proliferation of incoming metastatic cells relative to the recruitment of macrophages and bone-marrow derived cells? In what way is this process accelerated by ongoing damage repair? Better understanding of this, along with the development of a method to study it, will permit much more rational approaches toward blocking tumor metastasis.

描述（由申请人提供）：人们认为肺是某些转移性肿瘤播散的容许器官。最近的研究支持了这一点，发现远端原发性肿瘤刺激骨髓源性细胞（BMDC）迁移到肺部，形成转移前生态位（PreMN），这些细胞对于强健和有效的转移至关重要。这些研究使人们越来越认识到免疫系统和肺PreMN在肺转移中的重要性，但许多重要的问题仍然存在，并且迄今为止尚未解决。最值得注意的是，目前还没有直接的方法来评估肺PreMN内dtc与正常“不太允许”肺组织内dtc的行为和命运。此外，PreMN包含多种免疫细胞，与这些细胞群相互作用对DTC存活的影响尚不清楚。为了了解和治疗肺转移，我们必须首先在体内解决这些关键问题