The Extracellular Matrix in Tumor Progression and Metastasis

众所周知，细胞外基质(ECM)在肿瘤进展及其组织学过程中会发生显著变化。 临床表现被病理学家用作预后指标。显然，ECM既提供了结构性的、 对正常细胞和肿瘤细胞的物理和生化信号，对细胞增殖，存活， 分化和运动性--它对调节血管生成也是至关重要的。然而，我们并没有很好的 由于ECM的复杂性、交联性，对其在组织中的生化组成的了解 以及不溶性，这使得生化分析变得困难。这个小组开发了创新的方法来 结合新发展的生物信息学分析正常组织和肿瘤的体内基质 哺乳动物基因组中细胞外基质及其相关蛋白的最新分析 富含ECM的小鼠肿瘤模型和人类患者标本的蛋白质组学分析 从肿瘤银行来的。本申请中提出的这些方法和改进将用于研究 发生在肿瘤进展、侵袭、血管生成和治疗过程中的细胞外基质的组成和变化 转移。肿瘤细胞外基质的性质和来源(肿瘤细胞或间质细胞)将被描述和 相关的生长因子和细胞因子将被确定。蛋白质的功能作用令人感兴趣 肿瘤进展过程中的变化将使用功能丧失和功能获得手法进行分析。 这些将使用该小组在先前研究中开发的病毒载体来实现，这些病毒载体允许操纵 特定细胞中基因表达水平的上调或下调。除了让人们注意到 ECM蛋白的作用机制，这些研究可能确定干预肿瘤的靶点 进步。通过比较人类患者样本中细胞外基质和细胞外基质相关蛋白的图谱 (正常组织和肿瘤组织)，并将这些结果与肿瘤预后和对 治疗，希望有可能识别出

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