Impact of Cellular and Extracellular Host Components on Tumor Progression

描述（由申请人提供）：本申请寻求对四个相关研究项目的支持，这些项目侧重于使用人类肿瘤材料、细胞生物学方法和基因工程小鼠癌症模型（特别强调乳腺癌和肺癌）研究肿瘤微环境组分对原发性肿瘤和转移瘤进展的影响。肿瘤的微环境包含许多非肿瘤细胞，包括巨噬细胞、嗜中性粒细胞和肌成纤维细胞，并且其中几个项目使用小鼠模型和人类患者样本来研究这些细胞对肿瘤细胞行为的影响-包括局部来源的以及来自骨髓和其他地方的全身招募的细胞（例如，这些细胞的产生和运输将在小鼠模型和人类患者中使用复杂的体内成像方法进行分析。将研究募集和编程“反应性肿瘤基质”的这些细胞的分泌信号（生长因子和细胞因子），以及它们对肿瘤细胞的作用机制-诱导EMT、获得干细胞样性质、迁移、 侵袭、内渗和外渗以及转移瘤的形成。反应性基质还含有复杂的细胞外基质（ECM），其包括结合的生长因子和细胞因子，并且该ECM的组成在肿瘤进展期间显著变化-这些变化将使用新开发的蛋白质组学方法详细分析，并且其功能意义将通过操纵肿瘤和基质细胞中相关基因的表达来分析。四个项目负责人有着富有成效的互动和合作的历史，将通过TMEN的支持进一步加强。结合使用人类患者材料将发现锚到临床相关标准和小鼠模型中，以研究临床前试验中已识别相互作用的因果关系，这将允许单独使用两种系统都不可能。这些项目的共同目标是剖析肿瘤间质对肿瘤进展的细胞和非细胞影响，以期确定新的生物标志物和诊断和预后价值的特征以及潜在治疗干预的新靶点。

DESCRIPTION (provided by applicant): This application seeks support for four linked research projects focused on the influences of components of the tumor microenvironment on the progression of primary tumors and metastases using both human tumor materials, cell biological methods and genetically engineered mouse models of cancer, with particular emphasis on breast and lung cancer. The microenvironment of tumors contains many non-tumor cells, including macrophages, neutrophils and myofibroblasts and several of the projects use both mouse models and human patient samples to investigate the influences of these cells on the behavior of the tumor cells - both locally derived as well as systemically recruited cells from the bone marrow and elsewhere (e.g., spleen).The generation and trafficking of these cells will be analyzed using sophisticated in vivo imaging methods in both mouse models and human patients. The secreted signals (growth factors and cytokines) that recruit and program these cells of the "reactive tumor stroma" will be investigated as will be the mechanisms of their effects on the tumor cells - induction of EMT, acquisition of stem-cell-like properties, migration, invasion, intravasation and extravasation and formation of metastases. The reactive stroma also contains a complex extracellular matrix (ECM), which includes bound growth factors and cytokines and the composition of this ECM changes markedly during tumor progression - these changes will be analyzed in detail using newly developed proteomics methods and their functional significance will be analyzed by manipulating the expression of relevant genes in both tumor and stromal cells. The four project leaders have a history of productive interactions and collaborations that will be further enhanced by TMEN support. The combined use of human patient material to anchor the discoveries to clinically correlated criteria and mouse models for investigation of the causality of the identified interactions in pre-clinical tests will allow progess possible with neither system alone. The common goal of these projects will be to dissect the cellular and non-cellular effects of the tumor stroma on tumor progression with a view to identifying novel biomarkers and signatures of diagnostic and prognostic value and new targets for potential therapeutic intervention.