Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro
Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro
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DOI：
10.1073/pnas.0800835105
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发表时间：
2008-08-12
影响因子：
11.1
通讯作者：
Ingber, Donald E.
中科院分区：
文献类型：
--
作者：
Ghosh, Kaustabh;Thodeti, Charles K.;Ingber, Donald E.
肿瘤血管表现出异常的结构和功能，导致血流紊乱和间质压力升高，从而影响抗癌药物的输送。过去使肿瘤血管系统正常化的努力主要集中在抑制可溶性血管生成因子，如VEGF；然而，血管生成过程中毛细血管内皮细胞（CE）的生长和分化也受到细胞外基质（ECM）传递的机械力的影响。在这里，我们探讨了肿瘤CE细胞形成异常血管的可能性，因为它们失去了感知和响应这些物理信号的能力。这些研究表明，与正常CE细胞相比，肿瘤来源的CE细胞在暴露于单轴循环应变时不能重新定位其肌动蛋白细胞骨架，对ECM弹性变化表现出明显的形状敏感性，施加更大的牵引力，并在体外显示出更强的收缩柔性ECM底物和重组成管状网络的能力。这些行为与小GTPase Rho及其下游效应物Rho相关激酶（ROCK）的高水平基线活性相关。此外，通过使用ROCK抑制剂Y27632降低rho介导的张力，可以重新编程肿瘤CE细胞，使其对单轴循环应变的重新定向反应正常化，并使其在ECM凝胶上形成管状网络的能力正常化。因此，rho介导的肿瘤微环境中机械信号的异常感知可能会导致肿瘤CE细胞的异常行为，从而导致肿瘤微血管结构异常的发展。
Tumor blood vessels exhibit abnormal structure and function that cause disturbed blood flow and high interstitial pressure, which impair delivery of anti-cancer agents. Past efforts to normalize the tumor vasculature have focused on inhibition of soluble angiogenic factors, such as VEGF; however, capillary endothelial (CE) cell growth and differentiation during angiogenesis are also influenced by mechanical forces conveyed by the extracellular matrix (ECM). Here, we explored the possibility that tumor CE cells form abnormal vessels because they lose their ability to sense and respond to these physical cues. These studies reveal that, in contrast to normal CE cells, tumor-derived CE cells fail to reorient their actin cytoskeleton when exposed to uniaxial cyclic strain, exhibit distinct shape sensitivity to variations in ECM elasticity, exert greater traction force, and display an enhanced ability to retract flexible ECM substrates and reorganize into tubular networks in vitro. These behaviors correlate with a constitutively high level of baseline activity of the small GTPase Rho and its downstream effector, Rho-associated kinase (ROCK). Moreover, decreasing Rho-mediated tension by using the ROCK inhibitor, Y27632, can reprogram the tumor CE cells so that they normalize their reorientation response to uniaxial cyclic strain and their ability to form tubular networks on ECM gels. Abnormal Rho-mediated sensing of mechanical cues in the tumor microenvironment may therefore contribute to the aberrant behaviors of tumor CE cells that result in the development of structural abnormalities in the cancer microvasculature.