Strategies of Mesenchymal Invasion of Patient-derived Brain Tumors: Microenvironmental Adaptation.
Strategies of Mesenchymal Invasion of Patient-derived Brain Tumors: Microenvironmental Adaptation.
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DOI：
10.1038/srep24912
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发表时间：
2016-04-25
影响因子：
4.6
通讯作者：
Kim P
中科院分区：
文献类型：
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作者：
Cha J;Kang SG;Kim P
多形性胶质母细胞瘤（GBM）患者的高死亡率主要是由于广泛浸润到邻近组织和随后的快速复发。目前还没有明确的治疗策略，目标是浸润性亚群的GBM质量。使用间充质侵袭模式，已知GBM通过与脑微环境内的各种独特组分（例如富含透明质酸（HA）的基质和白色物质束）相互作用而广泛浸润。然而，目前还不清楚这些GBM微环境如何影响间充质入侵的策略。我们假设GBM有不同的策略，以促进这种入侵，通过适应他们的本地微环境。利用我们的三维GBM肿瘤球（TS）的体外仿生微环境平台，我们发现GBM侵袭的策略主要由富含HA的ECM微环境调节，在HA存在下显示出显著的表型变化，这主要是由HA合成酶（HAS）介导的。有趣的是，在HAS基因抑制后，GBM将其侵袭策略切换为粘着斑（FA）介导的侵袭。这些结果表明，微环境的适应允许GBM的灵活的入侵策略。使用我们的模型，我们提出了一个新的抑制途径，针对浸润性GBM，并提出了多靶点治疗GBM，这经历了微环境适应的重要性。
The high mortality in glioblastoma multiforme (GBM) patients is primarily caused by extensive infiltration into adjacent tissue and subsequent rapid recurrence. There are no clear therapeutic strategies that target the infiltrative subpopulation of GBM mass. Using mesenchymal mode of invasion, the GBM is known to widely infiltrate by interacting with various unique components within brain microenvironment such as hyaluronic acid (HA)-rich matrix and white matter tracts. However, it is unclear how these GBM microenvironments influence the strategies of mesenchymal invasion. We hypothesize that GBM has different strategies to facilitate such invasion through adaptation to their local microenvironment. Using our in vitro biomimetic microenvironment platform for three-dimensional GBM tumorspheres (TSs), we found that the strategies of GBM invasion were predominantly regulated by the HA-rich ECM microenvironment, showing marked phenotypic changes in the presence of HA, which were mainly mediated by HA synthase (HAS). Interestingly, after inhibition of the HAS gene, GBM switched their invasion strategies to a focal adhesion (FA)-mediated invasion. These results demonstrate that the microenvironmental adaptation allowed a flexible invasion strategy for GBM. Using our model, we suggest a new inhibitory pathway for targeting infiltrative GBM and propose an importance of multi-target therapy for GBM, which underwent microenvironmental adaptation.