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首页> 外文期刊>Molecular cancer research: MCR >SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions.
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SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions.

机译:SRC在三个方面调节肌动蛋白的动力学和恶性胶质细胞的侵袭。

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Malignant glioma is the major brain tumor in adults and has a poor prognosis. The failure to control invasive cell subpopulations may be the key reason for local glioma recurrence after radical tumor resection and may contribute substantially to the failure of the other treatment modalities such as radiation therapy and chemotherapy. As a model for this invasion, we have implanted spheroids from a human glioma cell line (U251) in three-dimensional collagen type I matrices, which these cells readily invade. We first observed that the Src family kinase-specific pharmacologic inhibitors PP2 and SU6656 significantly inhibited the invasion of the cells in this assay. We confirmed this result by showing that expression of two inhibitors of Src family function, dominant-negative-Src and CSK, also suppressed glioma cell invasion. To characterize this effect at the level of the cytoskeleton, we used fluorescent time-lapse microscopy on U251 cells stably expressing a YFP-actin construct and observed a rapid change in actin dynamics following addition of PP2 in both two-dimensional and three-dimensional cultures. In monolayer cultures, PP2 caused the disappearance of peripheral membrane ruffles within minutes. In three-dimensional cultures, PP2 induced the loss of actin bursting at the leading tip of the invadopodium. The inhibition of Src family activity is thus a potential therapeutic approach to treat highly invasive malignant glioma.
机译:恶性神经胶质瘤是成人的主要脑肿瘤,预后较差。无法控制侵袭性细胞亚群可能是根治性肿瘤切除后局部神经胶质瘤复发的关键原因,并且可能在很大程度上导致其他治疗方式的失败,例如放射疗法和化学疗法。作为这种侵袭的模型,我们将人胶质瘤细胞系(U251)的球状体植入了三维I型胶原蛋白基质中,这些细胞易于入侵。我们首先观察到Src家族激酶特异性药理抑制剂PP2和SU6656在此测定法中显着抑制了细胞的侵袭。我们通过显示两种Src家族功能抑制剂(显性负Src和CSK)的表达也抑制了胶质瘤细胞的侵袭,证实了这一结果。为了在细胞骨架水平上表征这种作用,我们在稳定表达YFP-肌动蛋白构建体的U251细胞上使用了荧光延时显微镜,并观察了在二维和三维培养物中添加PP2后肌动蛋白动力学的快速变化。 。在单层培养中,PP2导致几分钟内外周膜褶皱消失。在三维培养物中,PP2诱导肌动蛋白在创足前部尖端破裂的损失。因此,抑制Src家族活性是治疗高侵袭性恶性神经胶质瘤的潜在治疗方法。

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