David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, U.S.A.
Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, U.S.A.
Sci Rep. 2017 Jan 10;7:40495. doi: 10.1038/srep40495.
The angiogenic switch, the time at which a tumor becomes vascularized, is a critical step in tumor progression. Indeed, without blood supply, tumors will fail to grow beyond 1 mm and are unlikely to disseminate. The extracellular matrix (ECM), a major component of the tumor microenvironment, is known to undergo significant changes during angiogenesis and tumor progression. However the extent of these changes remains unknown. In this study, we used quantitative proteomics to profile the composition of the ECM of pancreatic islets in a mouse model of insulinoma characterized by a precisely timed angiogenic switch. Out of the 120 ECM proteins quantified, 35 were detected in significantly different abundance as pancreatic islets progressed from being hyperplastic to angiogenic to insulinomas. Among these, the core ECM proteins, EFEMP1, fibrillin 1, and periostin were found in higher abundance, and decorin, Dmbt1, hemicentin, and Vwa5 in lower abundance. The angiogenic switch being a common feature of solid tumors, we propose that some of the proteins identified represent potential novel anti-angiogenic targets. In addition, we report the characterization of the ECM composition of normal pancreatic islets and propose that this could be of interest for the design of tissue-engineering strategies for treatment of diabetes.
血管生成开关是肿瘤血管化的时间点，是肿瘤进展的关键步骤。事实上，如果没有血液供应，肿瘤将无法长到超过 1 毫米，也不太可能扩散。细胞外基质 (ECM) 是肿瘤微环境的主要组成部分，已知在血管生成和肿瘤进展过程中会发生显著变化。然而，这些变化的程度仍不清楚。在这项研究中，我们使用定量蛋白质组学来分析胰岛素瘤小鼠模型中胰岛 ECM 的组成，该模型具有精确计时的血管生成开关。在定量的 120 种 ECM 蛋白中，有 35 种在胰岛从增生到血管生成到胰岛素瘤的过程中丰度差异显著。在这些蛋白中，核心 ECM 蛋白 EFEMP1、纤维连接蛋白 1 和 periostin 的丰度较高，而 decorin、Dmbt1、hemicentin 和 Vwa5 的丰度较低。血管生成开关是实体瘤的共同特征，我们提出，其中一些蛋白可能代表潜在的新型抗血管生成靶点。此外，我们还报告了正常胰岛 ECM 组成的特征，并提出这可能对糖尿病治疗的组织工程策略的设计具有重要意义。
