The Extracellular Matrix in Tumor Progression and Metastasis

已知细胞外基质（ECM）在肿瘤进展过程中显著变化，并且其组织学改变与肿瘤的病理学改变有关。 临床表现被病理学家用作预后指标。很明显，ECM提供了结构， 对正常细胞和肿瘤细胞的物理和生物化学线索，对细胞增殖，存活， 分化和运动-它也是调节血管生成的关键。然而，我们没有一个好的 由于ECM的复杂性、交联性和生物相容性， 和不溶性，这使得生化分析变得困难。该小组开发了创新的方法， 通过结合新开发的生物信息学技术分析正常组织和肿瘤的体内基质， 用最新技术分析哺乳动物基因组中编码的ECM和ECM相关蛋白 来自小鼠癌症模型和人类患者材料的ECM富集样品的蛋白质组学分析 从肿瘤银行。本申请中提出的这些方法和改进将用于调查 在肿瘤进展、侵袭、血管生成和转移过程中发生的ECM的组成和变化， 转移将表征肿瘤ECM的性质和起源（肿瘤细胞或基质细胞）， 将鉴定相关的生长因子和细胞因子。蛋白质的功能作用显示出有趣的 将使用功能丧失和获得操作来分析肿瘤进展期间的变化。 这些将使用该小组在先前研究中开发的允许操纵的病毒载体来实现 特定细胞中基因表达水平的变化。除了揭示 ECM蛋白的功能机制，这些研究可能会确定干预肿瘤的靶点， 进展通过比较人类患者样本中ECM和ECM相关蛋白的谱， （正常和肿瘤组织），并将这些结果与肿瘤结果和对肿瘤治疗的反应的临床数据相关联。 治疗，希望有可能确定

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