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）：据信肺是某些转移肿瘤播种的允许器官。最近的研究支持了这一点，发现远端原发性肿瘤会激发骨髓衍生的细胞（BMDC）迁移到肺中，形成了一种前转移的小裂（PREMN），并且这些细胞对于稳健，有效的转移至关重要。这些研究导致人们对免疫系统和肺部PREMN在肺转移中的重要性的认识日益认识，但是仍然存在许多重要问题，迄今为止一直无法访问。最值得注意的是，没有直接的方法可以评估肺Premn中DTC的行为和命运与正常的“丧偶”肺组织。此外，PREMN包含各种免疫细胞，与这些人群相互作用对DTC存活的影响尚不清楚。为了理解和治疗靶向肺转移，我们必须首先解决这些关键问题，体内 这种R21探索性授予的基础是应用新型的实时浸润成像方法来了解肺如何处理传入细胞。特别是要了解转移细胞在环境中的生存以及宿主细胞如何“接收”它们并保护它们免受脉管系统中的正常消除细胞的方式。我们假设从微脉管系统中正常去除细胞是一种修复过程，该过程由宿主细胞帮助的转移性细胞延长了持续时间以实现成功定植。 该项目的总体成功将取决于我们对转移细胞到达肺部时的时空景观的了解。是肿瘤细胞接下来是由“助手”宿主细胞连接的，还是成功地被这些细胞捕获的MetS？与巨噬细胞和骨髓衍生的细胞的募集相对于传入转移细胞增殖的动力学是什么？持续的损害维修以什么方式加速了这个过程？更好地理解这一点，以及一种研究方法的发展，将允许更加理性的方法来阻断肿瘤转移。