The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells.
The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells.
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DOI：
10.1158/0008-5472.can-08-4859
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Ulrich TA;de Juan Pardo EM;Kumar S
多形性胶质母细胞瘤（GBM）是一种中枢神经系统恶性星形细胞瘤，即使采用积极治疗，中位生存时间也为15个月。这种快速进展部分是由于单个肿瘤细胞扩散浸润到脑实质中，这被认为涉及肿瘤细胞和细胞外基质（ECM）之间的异常相互作用。在这里，我们测试的假设，机械线索从ECM有助于关键肿瘤细胞特性相关的入侵。我们培养了一系列的胶质瘤细胞系（U373-MG，U87-MG，U251-MG，SNB 19，C6）的纤连蛋白包被的聚合物ECM基板定义的机械刚度和ECM刚度的作用，在调节肿瘤细胞的结构，迁移和增殖。在高度刚性的ECM上，肿瘤细胞广泛扩散，形成突出的应力纤维和成熟的局灶性粘连，并迅速迁移。由于ECM硬度降低到与正常脑组织相当的值，肿瘤细胞呈现圆形并且不能有效地迁移。值得注意的是，细胞增殖也受到ECM刚性的强烈调控，细胞在刚性ECM上分裂的速度比柔顺ECM快得多。药理学抑制非肌肉肌球蛋白II为基础的收缩性钝化这种刚性敏感性和救援高度顺应性基板上的细胞运动。总的来说，我们的研究结果为一种新的模型提供了支持，在该模型中，ECM刚性提供了一种变革性的微环境线索，该线索通过肌动球蛋白收缩性来调节GBM肿瘤细胞的侵袭性。
Glioblastoma multiforme (GBM) is a malignant astrocytoma of the central nervous system associated with a median survival time of 15 months, even with aggressive therapy. This rapid progression is due in part to the diffuse infiltration of single tumor cells into the brain parenchyma, which is thought to involve aberrant interactions between tumor cells and the extracellular matrix (ECM). Here we test the hypothesis that mechanical cues from the ECM contribute to key tumor cell properties relevant to invasion. We cultured a series of glioma cell lines (U373-MG, U87-MG, U251-MG, SNB19, C6) on fibronectin-coated polymeric ECM substrates of defined mechanical rigidity and investigated the role of ECM rigidity in regulating tumor cell structure, migration, and proliferation. On highly rigid ECMs, tumor cells spread extensively, form prominent stress fibers and mature focal adhesions, and migrate rapidly. As ECM rigidity is lowered to values comparable to normal brain tissue, tumor cells appear rounded and fail to productively migrate. Remarkably, cell proliferation is also strongly regulated by ECM rigidity, with cells dividing much more rapidly on rigid than compliant ECMs. Pharmacological inhibition of nonmuscle myosin II-based contractility blunts this rigidity-sensitivity and rescues cell motility on highly compliant substrates. Collectively, our results provide support for a novel model in which ECM rigidity provides a transformative, microenvironmental cue that acts through actomyosin contractility to regulate the invasive properties of GBM tumor cells.