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

描述(申请人提供)：据信肺是播种某些转移性肿瘤的允许器官。最近的研究支持这一点，发现远端原发肿瘤促使骨髓衍生细胞(BMDC)迁移到肺内，形成转移前生态位(PreMN)，这些细胞对于强大而有效的转移至关重要。这些研究使人们越来越多地认识到免疫系统和肺前MN在肺转移中的重要性，但许多重要的问题仍然存在，到目前为止还无法解决。最值得注意的是，目前还没有直接的方法来评估肺PreMN内DCs的行为和命运，以及正常肺组织中DCs的行为和命运。此外，PreMN含有一组不同的免疫细胞，与这些群体相互作用对DTC存活的影响尚不清楚。为了了解和治疗肺转移，我们必须首先在活体内解决这些关键问题。 这项R21探索性拨款的基础是应用新的实时活体成像方法来了解肺如何处理传入细胞。尤其重要的是要了解转移细胞为什么以及如何在环境中存活，以及宿主细胞如何‘接收’它们，并保护它们免受正常的细胞从血管系统中消除的影响。我们假设，从微血管中正常去除细胞是一个修复过程，转移的细胞在宿主细胞的帮助下，延长持续时间以实现成功的定植。 这个项目的总体成功将取决于我们对转移细胞到达肺部时所面临的时空格局的了解。肿瘤细胞是先被“辅助”宿主细胞植入，还是由这些细胞直接捕获成功的甲硫氨酸？相对于巨噬细胞和骨髓来源细胞的募集，传入转移细胞的增殖动力学是什么？正在进行的损害修复以什么方式加速了这一过程？更好地理解这一点，以及研究它的方法的发展，将允许更合理的方法来阻止肿瘤转移。 公共卫生相关性：这项建议将应用新的活体内肺部成像来确定转移细胞到达小鼠肺内后的第一个小时。由于我们对转移性肿瘤细胞在这种环境中存活的原因知之甚少，这是决定如何降低它们的成功率的一项重大任务。

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. PUBLIC HEALTH RELEVANCE: This proposal will apply novel intravital imaging of the lung to define the first hours following the arrival of metastatic cells into the mouse lung. As we know very little about why metastatic tumor cells survive in this environment, this represents a major undertaking in determining how to decrease their success.