The Extracellular Matrix in Tumor Progression and Metastasis

肿瘤进展和转移中的细胞外基质

• 批准号: 8555483
• 负责人: RICHARD O HYNES
• 金额: $ 23.59万
• 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/8555483
• 关键词: Address; Antibodies; Biochemical; Bioinformatics; Breast; Cataloging; Catalogs; Cell Proliferation; Cells; Clinical; Clinical Data; Collaborations; Complement; Coupling; Cues; Diagnostic; Extracellular Matrix; Extracellular Matrix Proteins; Gene Expression; Goals; Growth Factor; Human; Human Genome; Intervention; Islets of Langerhans; Knock-out; Light; Lung; Mass Spectrum Analysis; Methods; Modeling; Mus; Nature; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Outcome; Pathologist; Patients; Peptides; Primary Neoplasm; Proteins; Proteolysis; Proteomics; Regulation; Research; Role; Sampling; Source; Staging; Stromal Cells; Tissue Extracts; Tissues; Tumor Bank; Tumor Tissue; Viral Vector; angiogenesis; anticancer research; cell motility; chemotherapy; crosslink; cytokine; extracellular; gain of function; human cancer mouse model; in vivo; innovation; interest; mammalian genome; matrigel; mouse genome; neoplastic cell; overexpression; prognostic; prognostic indicator; response; tumor; tumor progression

The extracellular matrix (ECM) is known to change markedly during tumor progression and its histological presentation is used as a prognostic indicator by pathologists. It is clear that the ECM provides both structural, physical and biochemical cues to both normal and tumor cells, with major effects on cell proliferation, survival, differentiation and motility - it is also crucial for regulation of angiogenesis. However, we do not have a good understanding of the biochemical composition of the ECM in tissues because of its complexity, crosslinking and insolubility that make biochemical analyses difficult. This group has developed innovative methods for analyzing the in vivo matrix of normal tissues and tumors by combining newly developed bioinformatic analyses of the ECM and ECM-associated proteins encoded in mammalian genomes with state-of-the-art proteomics analyses of ECM-enriched samples from mouse models of cancer and from human patient material from tumor banks. These methods and improvements proposed in this application will be used to investigate the composition and changes in ECM that occur during tumor progression, invasion, angiogenesis and metastasis. The nature and origins (tumor cells or stromal cells) of the tumor ECM will be characterized and associated growth factors and cytokines will be identified. The functional roles of proteins showing interesting changes during tumor progression will be analyzed using loss- and gain-of-function manipulations. These will be implemented using viral vectors developed in prior research by this group that allow manipulation of the levels of gene expression in specific cells either up or down. In addition to shedding light on the mechanisms of function of ECM proteins, these studies may identify targets for intervention in tumor progression. By comparing the profiles of ECM and ECM-associated proteins in human patient samples (normal and tumor tissues) and correlating those results with clinical data on tumor outcomes and response to therapy, it is hoped that it will be possible to identify

已知细胞外基质（ECM）在肿瘤进展过程中明显变化及其组织学 病理学家将演示用作预后指标。显然，ECM既提供结构性， 正常细胞和肿瘤细胞的物理和生化线索，对细胞增殖，存活， 分化和运动性 - 这对于调节血管生成也至关重要。但是，我们没有好的 由于其复杂性而对ECM的生化组成的理解，交联 和使生化分析变得困难的不溶性。该小组开发了创新方法 通过结合新开发的生物学来分析正常组织和肿瘤的体内基质 对哺乳动物基因组编码的ECM和ECM相关蛋白的分析 来自癌症小鼠模型和人类患者材料的ECM富集样品的蛋白质组学分析 来自肿瘤库。本应用程序中提出的这些方法和改进将用于调查 在肿瘤进展，侵袭，血管生成和 转移。肿瘤ECM的性质和起源（肿瘤细胞或基质细胞）将被表征，并且 将确定相关的生长因子和细胞因子。蛋白质的功能作用显示有趣 肿瘤进展过程中的变化将使用损失和功能获得的操作分析。 这些将使用该小组的先前研究中开发的病毒向量来实施，以操纵 在特定细胞中的基因表达水平上或向下。除了向 ECM蛋白功能的机理，这些研究可能鉴定出干预肿瘤的靶标 进展。通过比较人类患者样品中ECM和ECM相关蛋白的曲线 （正常和肿瘤组织），并将这些结果与肿瘤结局的临床数据相关联和对 治疗，希望可以识别