3D-Adhesion Stromagenesis in Cancer Permissiveness

描述(申请人提供)：肿瘤微环境在肿瘤的发生和发展中起着至关重要的作用。肿瘤通过调节成纤维细胞基质细胞在肿瘤发展过程中改变基质细胞外基质(ECM)的形态和分子组成。间质的这些物理和生化变化影响原始间质细胞的特性，使其活化，并为间质激活提供燃料，从而促进癌细胞的发展。肿瘤和间质之间的重要相互作用意味着，原则上，有可能针对调控肿瘤诱导的间质激活的信号通路，从而遏制肿瘤的发生。 我们已经开发了3D体外系统和体外系统，该系统包括3D细胞在基质成纤维细胞或脱细胞致瘤组织ECM中的基质中。使用这些系统，我们不仅观察到间质基质随着肿瘤的发展而改变，而且肿瘤基质是诱导正常成纤维细胞显示肿瘤相关成纤维细胞特性的必要条件和充分条件。在过去，我们表明整合素依赖的信号通路的改变对促进肿瘤间质的发展至关重要，并且可以通过靶向基本间质成分来抑制肿瘤细胞的侵袭。在与一组专注于肾癌的临床研究人员的合作下，我们开发了广泛的资源来剖析这种疾病中间质与肿瘤的相互作用。提供的初步结果：一种蛋白质组特征，定义了一组蛋白质，包括赖氨酰氧化酶(LOX)和Periostin，在肿瘤相关的ECM中特异性上调，并发现Palladin基质表达高度预测肾癌的肿瘤预后。在这项研究中，我们建议： 1.验证肿瘤相关细胞外基质的特定结构和生化成分协同诱导幼稚成纤维细胞表型转换的假设。 2.确定Palladin在肿瘤相关的而不是正常的ECM诱导的特异性整合素串扰调节的表型转换中的作用。 3.评价肾细胞癌(RCC)间质激活的临床意义。 公共卫生相关性：这项研究的结果将有助于揭示导致肿瘤刺激恶性循环的一些机制，该恶性循环维持间质激活，进而刺激肿瘤进展。这项研究将强调评估间充质间质进展的临床相关性，并可能揭示防止间质进展从而延缓肿瘤发生的可能靶点。

DESCRIPTION (provided by applicant): The tumor microenvironment plays a crucial role in tumor development and progression. Tumors alter the topography and molecular composition of stromal extracellular matrix (ECM) by regulation of fibroblastic stromal cells during tumor development. These physical and biochemical alterations of the stroma affect the properties of naive stromal cells to become activated and fuel stromal activation thus promoting cancer cell progression. The vital interplay between tumor and stroma means that, in principle, it is possible to target signaling pathways that regulate tumor-induced stroma activation and thereby contain tumorigenesis. We have developed 3D in vitro and an ex vivo systems comprising cells plated in 3D in matrices derived from stromal fibroblasts or in decellularized tumorigenic tissue ECMs. Using these systems, we have not only observed that stromal matrices are modified as the tumor develops but that tumor matrices are both necessary and sufficient to induce normal fibroblasts to display properties characteristic of tumor-associated fibroblasts. In the past we showed that alterations in integrin-dependent signaling pathways are critical to the development of tumor-promoting stroma and that tumor cell invasion can be repressed by targeting fundamental stroma components. In collaboration with a team of clinical researchers focused on kidney cancer, we have developed extensive resources to dissect stromal-tumor interactions in this disease. Preliminary results rendered: a proteomic signature that has defined a group of proteins including lysyl oxidase (LOX), and periostin as specifically upregulated in tumor-associated ECM, and identified palladin stromal expression as highly predictive of tumor prognosis in renal cancer. In this study we propose to: 1. Test the hypothesis that specific structural and biochemical components of the tumor-associated ECM collaborate to induce a phenotypic switch in naive fibroblasts. 2. Establish the role for palladin in the phenotypic switch regulated by specific integrin crosstalk induced by tumor-associated but not normal ECM. 3. Assess the clinical importance of stromal activation in human renal cell carcinoma (RCC). PUBLIC HEALTH RELEVANCE: Results stemming from this study will facilitate uncovering some of the mechanisms responsible for the tumor fueling vicious cycle which maintains stroma activation and in turn incites tumor progression. The study will emphasize the clinical relevance of assessing the progression of mesenchymal stroma, and it could reveal possible targets to prevent stroma progression and consequently stall tumorigenesis.