Impact of Cellular and Extracellular Host Components on Tumor Progression

细胞和细胞外宿主成分对肿瘤进展的影响

• 批准号: 8337799
• 负责人: RICHARD O HYNES
• 金额: $ 73.42万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337799
• 关键词: Address; Adhesions; Affect; Aggressive behavior; Area; Behavior; Binding; Biochemical; Biological; Biological Markers; Biology; Biopsy; Blood Circulation; Bone Marrow; Bone Marrow Cells; Breast Cancer Model; Cancer Model; Cell model; Cell physiology; Cells; Cellular biology; Chest; Clinical; Clinical Data; Collaborations; Collection; Complex; Data; Development; Diagnostic; Distant; Doctor of Philosophy; Endocrine; Epithelial; Etiology; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Extramedullary; Extravasation; Fibroblasts; Funding; General Hospitals; Generations; Genes; Genetically Engineered Mouse; Goals; Growth Factor; Hematopoietic; Human; Individual; Inflammatory; Institutes; Instruction; Integrins; Invaded; Investigation; Laboratories; Link; Lung Adenocarcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Massachusetts; Medicine; Mesenchymal; Methods; Modeling; Molecular; Mus; Myeloid Cells; Myofibroblast; Nature; Neoplasm Metastasis; Neoplastic Epithelial Cell; Neoplastic Stromal Cell; Non-Small-Cell Lung Carcinoma; Normal Cell; Oncologist; Organ; Paracrine Communication; Pathogenesis; Patients; Phenotype; Physiological; Play; Primary Neoplasm; Process; Property; Proteins; Proteomics; Reagent; Recording of previous events; Recruitment Activity; Research; Research Project Grants; Role; Sampling; Signal Transduction; Site; Spleen; Splenomegaly; Stem cells; Stromal Cells; System; Systems Biology; Tenascin; Testing; Therapeutic Intervention; Tissue Microarray; Tissue Sample; Tissues; Tumor Bank; Tumor Tissue; Work; base; behavior influence; cancer cell; cell type; college; cytokine; extracellular; granulocyte; host neoplasm interaction; human tissue; imaging modality; in vivo; innovation; loss of function; macrophage; malignant breast neoplasm; migration; monocyte; mouse model; neoplastic cell; neutrophil; novel; overexpression; pre-clinical; precursor cell; prognostic; prognostic indicator; programs; release factor; response; stem; trafficking; trait; tumor; tumor progression; working group

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.

描述（由申请人提供）：本申请旨在支持四个相关的研究项目，重点关注肿瘤微环境成分对原发肿瘤和转移进展的影响，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。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，一些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——包括局部来源的细胞以及从骨髓和其他地方（如脾脏）系统募集的细胞。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。分泌的信号（生长因子和细胞因子）招募和编程这些细胞的“反应性肿瘤基质”将被研究，以及它们对肿瘤细胞的作用机制-诱导EMT，获得干细胞样特性，迁移，