Impact of Cellular and Extracellular Host Components on Tumor Progression

描述(申请人提供)：本申请寻求支持四个相互关联的研究项目，重点是肿瘤微环境的组成部分对原发肿瘤和转移的影响，使用人类肿瘤材料、细胞生物学方法和癌症的基因工程小鼠模型，特别是乳腺癌和肺癌。肿瘤的微环境包含许多非肿瘤细胞，包括巨噬细胞、中性粒细胞和肌成纤维细胞，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，这些细胞既包括局部来源的细胞，也包括来自骨髓和其他地方(如脾)的系统募集的细胞。这些细胞的生成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。将研究招募和编程这些“反应性肿瘤间质”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，获得干细胞样属性，迁移， 侵袭、渗入、渗出和转移的形成。反应性间质还含有复杂的细胞外基质(ECM)，其中包括结合的生长因子和细胞因子，这种ECM的组成在肿瘤进展过程中发生显著变化-这些变化将使用新开发的蛋白质组学方法进行详细分析，并将通过调控相关基因在肿瘤和间质细胞中的表达来分析它们的功能意义。这四位项目负责人有着卓有成效的互动和合作的历史，这些互动和合作将在TMAN的支持下得到进一步加强。联合使用人类患者材料将发现固定在临床相关标准和小鼠模型上，以研究临床前试验中已识别的相互作用的因果关系，这将允许仅靠这两个系统都不可能取得进展。这些项目的共同目标将是剖析肿瘤间质对肿瘤进展的细胞和非细胞影响，以期确定新的诊断和预后价值的生物标志物和标志，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.