Fibronectin matrix assembly suppresses dispersal of glioblastoma cells.
Fibronectin matrix assembly suppresses dispersal of glioblastoma cells.
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DOI：
10.1371/journal.pone.0024810
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Foty RA
中科院分区：
文献类型：
--
作者：
Sabari J;Lax D;Connors D;Brotman I;Mindrebo E;Butler C;Entersz I;Jia D;Foty RA
胶质母细胞瘤（GBM）是最具侵袭性和最常见的原发性脑肿瘤，中位生存期为12-15个月。由于肿瘤细胞在大脑内广泛分散，手术切除、放疗和化疗很难治愈。防止扩散可能对治疗有益。先前的研究报道，增加细胞-细胞内聚可以通过阻止细胞脱离肿瘤肿块而显著减少侵袭。我们之前报道过α5β1整合素-纤维连接蛋白相互作用是间接细胞-细胞内聚的强大介质，并且纤维连接蛋白基质组装（FNMA）过程对于在三维肿瘤样球体中建立细胞之间的强结合至关重要。在这里，我们探讨了FNMA在防止GBM细胞从肿瘤样肿块扩散中的潜在作用。利用一系列gbm衍生的细胞系，我们开发了一种体外实验来测量聚集体在固体基质上的扩散速度。尽管它们的病理分级相似，但来自这些细胞系的聚集体以明显不同的速度扩散。传播速度与FNMA容量成反比，在GBM细胞中恢复FNMA可以通过保持细胞更多的连接来显着降低传播速度。在FNMA修复的细胞中使用70 KDa的纤维连接蛋白片段阻断FNMA，可以恢复传播速度，从而确立FNMA在介导传播中的功能作用。总的来说，数据支持FNMA恢复与扩散速度降低之间的功能因果关系。这是首次证明FNMA可以抑制GBM的扩散。
Glioblastoma (GBM), the most aggressive and most common form of primary brain tumor, has a median survival of 12–15 months. Surgical excision, radiation and chemotherapy are rarely curative since tumor cells broadly disperse within the brain. Preventing dispersal could be of therapeutic benefit. Previous studies have reported that increased cell-cell cohesion can markedly reduce invasion by discouraging cell detachment from the tumor mass. We have previously reported that α5β1 integrin-fibronectin interaction is a powerful mediator of indirect cell-cell cohesion and that the process of fibronectin matrix assembly (FNMA) is crucial to establishing strong bonds between cells in 3D tumor-like spheroids. Here, we explore a potential role for FNMA in preventing dispersal of GBM cells from a tumor-like mass. Using a series of GBM-derived cell lines we developed an in vitro assay to measure the dispersal velocity of aggregates on a solid substrate. Despite their similar pathologic grade, aggregates from these lines spread at markedly different rates. Spreading velocity is inversely proportional to capacity for FNMA and restoring FNMA in GBM cells markedly reduces spreading velocity by keeping cells more connected. Blocking FNMA using the 70 KDa fibronectin fragment in FNMA-restored cells rescues spreading velocity, establishing a functional role for FNMA in mediating dispersal. Collectively, the data support a functional causation between restoration of FNMA and decreased dispersal velocity. This is a first demonstration that FNMA can play a suppressive role in GBM dispersal.
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