Tumor Microenvironment and Metastasis

肿瘤微环境和转移计划重点关注癌细胞及其微环境之间的相互作用，这些微环境是肿瘤细胞侵入周围组织，穿透血管并最终进入并在远处组织中生长的潜力的决定因素。研究旨在阐明单核细胞、巨噬细胞、内皮细胞和癌细胞及其支持基质之间的信号传导途径和机械相互作用，这有助于转移表型。该项目的目标是：（1）剖析微环境在肿瘤进展和转移中的作用，特别是巨噬细胞亚群在肿瘤进展的各个阶段和要素中的贡献;（2）阐明生长因子和细胞因子在调节细胞迁移、播散、血管生成和原发性肿瘤细胞侵袭远端部位中的分子机制; 3）评估表面分子如钙粘蛋白和膜表面寡糖在肿瘤进展中的作用;（4）通过开发（i）参与调节体内细胞迁移的途径的活性状态的荧光生物传感器和（ii）用于定量长期跟踪原发性肿瘤中光标记的不同细胞群的光开关蛋白，以及（5）将这些发现转化为预测转移潜力和风险并鉴定治疗靶点的人体组织相关研究。新的成像技术是在Gruss Lipper生物光子学中心开发的，该中心为该计划提供了独特的工具，这些工具通过分析成像共享资源提供给更广泛的AECC社区。实验方法的本质是开发具有荧光标记细胞谱系的新型小鼠转基因模型。该项目成员的研究主要集中在乳腺癌上，尽管也研究了其他肿瘤类型。该计划的研究部分得到了计划项目资助的支持，该项目资助反映并促进了该计划成员的合作研究。目前有来自11个部门的24名成员，其中10名是新加入该计划的，由22个NCI赠款（410万美元直接）和18个其他同行评审的癌症相关赠款（350万美元直接）支持。自上次CCSG审查以来，该计划成员发表了239篇癌症相关研究论文，其中23%来自计划内，28%来自计划间出版物。

PROJECT SUMMARY (See instructions): The Tumor Microenvironment and Metastasis Program focuses on the interactions between cancer cells and their microenvironment that are determinants of the potential of tumor cells to invade surrounding tissues, penetrate blood vessels, and ultimately enter and grow in distant tissues. Studies are directed to deciphening the signaling pathways and mechanical interactions among monocytes, macrophages, endothelial cells and carcinoma cells, and each of their supporting stroma, which contribute to the metastatic phenotype. The goals of the program are to: (1) Dissect the role the microenvironment in tumor progression and metastasis, in particular, the contribution of macrophage subpopulations to the various phases and elements of tumor progression; 2) to elucidate the molecular mechanisms of growth factor and cytokine action in regulating cell migration, dissemination, angiogenesis and invasion of distant sites by primary tumor cells; 3) to assess the role of surface molecules, such a cadherins and membrane surface oligosaccharides, in tumor progression; (4) to characterize the biochemical and structural properties of molecules that regulate cytoskeletal proteins involved in tumor cell and macrophage motility through the development of (i) fluorescent biosensors of the activity status of pathways involved in regulating cell migration in vivo and (ii) photo-switchable proteins for quantitative long-term tracking of distinct groups of cells photomarked in the primary tumor and (5) to translate these findings into correlative studies with human tissues that are predictive of metastatic potential and risk, and that identify therapeutic targets. New imaging technologies are developed in the Gruss Lipper Biophotonics Center that provides this program with unique tools that are made available to the broader AECC community through the Analytical Imaging Shared Resource. Intrinsic to the experimental approach is the development of novel mouse transgenic models with fluorescently-labeled cellular lineages. The research by members of this program is integrated by a major shared focus on breast cancer, although other tumor types are studied as well. Research in this program is supported, in part, by a program project grant which reflects, and furthers, the collaborative research of members of this program. There are currently 24 members from 11 departments, of whom 10 are new to the program, supported by 22 NCI grants ($4.1M Direct) and 18 other peer-reviewed cancer-relevant grants ($3.5M Direct). Since the last CCSG review there have been 239 cancer-relevant research papers by members of this program of which 23% represent intraprogrammatic, and 28% represent interprogrammatic publications.