Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth.
Recapitulating the human tumor microenvironment: Colon tumor-derived extracellular matrix promotes angiogenesis and tumor cell growth.
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DOI：
10.1016/j.biomaterials.2016.11.034
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发表时间：
2017-02
期刊：
影响因子：
14
通讯作者：
Hughes CC
中科院分区：
文献类型：
--
作者：
Romero-López M;Trinh AL;Sobrino A;Hatch MM;Keating MT;Fimbres C;Lewis DE;Gershon PD;Botvinick EL;Digman M;Lowengrub JS;Hughes CC
细胞外基质（ECM）是所有组织的基本和动态组成部分，并通过提供机械和生化信号线索直接影响细胞行为。ECM的变化可以改变组织的稳态，潜在地导致促进细胞转化和肿瘤的产生。因此，了解癌症进展过程中ECM成分的变化对靶向治疗的发展至关重要。先前复制天然3D细胞微环境的努力利用了蛋白质凝胶和支架，这些蛋白质凝胶和支架不完全重现天然组织的复杂性。在这里，我们解决这个问题，提取和比较ECM从正常人结肠和结肠肿瘤转移到肝脏。我们发现蛋白质组成和硬度的差异，并观察到血管网络形成和肿瘤生长的显着差异，在体外和体内的每个重建的矩阵。我们使用荧光寿命成像显微镜研究了肿瘤和内皮细胞中NADH的游离/结合比，作为细胞代谢状态的替代。我们观察到接种在肿瘤ECM中的细胞比接种在正常ECM中的细胞具有更高的游离NADH相对水平，这与更高的糖酵解速率一致。这些结果表明，ECM在癌细胞及其相关脉管系统的生长中起重要作用。
Extracellular matrix (ECM) is an essential and dynamic component of all tissues and directly affects cellular behavior by providing both mechanical and biochemical signaling cues. Changes in ECM can alter tissue homeostasis, potentially leading to promotion of cellular transformation and the generation of tumors. Therefore, understanding ECM compositional changes during cancer progression is vital to the development of targeted treatments. Previous efforts to reproduce the native 3D cellular microenvironment have utilized protein gels and scaffolds that incompletely recapitulate the complexity of native tissues. Here, we address this problem by extracting and comparing ECM from normal human colon and colon tumor that had metastasized to liver. We found differences in protein composition and stiffness, and observed significant differences in vascular network formation and tumor growth in each of the reconstituted matrices, both in vitro and in vivo. We studied free/bound ratios of NADH in the tumor and endothelial cells using Fluorescence Lifetime Imaging Microscopy as a surrogate for the metabolic state of the cells. We observed that cells seeded in tumor ECM had higher relative levels of free NADH, consistent with a higher glycolytic rate, than those seeded in normal ECM. These results demonstrate that the ECM plays an important role in the growth of cancer cells and their associated vasculature.