Servotte S, Camby I, Debeir O, Deroanne C, Lambert C A, Lapière C M, Kiss R, Nusgens B, Decaestecker C
Laboratory of Toxicology, Institute of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.
Neuropathol Appl Neurobiol. 2006 Dec;32(6):575-84. doi: 10.1111/j.1365-2990.2006.00760.x.
Astrocytic tumours are associated with dismal prognoses due to their pronounced ability to diffusely invade the brain parenchyma. Various neuropeptides, including gastrin, are able to modulate tumour astrocyte migration. While neurotensin has been shown to influence the proliferation of glioma cells and the migratory ability of a large set of other cell types, its role in glioma cell migration has never been investigated. Neurotensin-induced modifications to the motility features of human U373 glioblastoma cells therefore constitute the topic of the present study. We evidenced that three subtypes of neurotensin receptors (NTR1, NTR2 and NTR3) are expressed in U373 glioblastoma cells, at least as far as their mRNAs are concerned. Treating U373 tumour cells with 10 nM neurotensin markedly modified the morphological patterns of these cells and also profoundly altered the organization of their actin cytoskeletons. Pull-down assays revealed that neurotensin induced the activation in U373 cells of both Rac1 and Cdc42 but not RhoA. Scratch wound assays evidenced that neurotensin (0.1 and 10 nM) very significantly inhibited wound colonization by U373 cells cultured in the absence of serum. In addition, quantitative phase-contrast videomicroscopy analyses showed that neurotensin decreases the motility levels of U373 glioblastoma cells when these cells are cultured on plastic. In sharp contrast, neurotensin stimulates the motility of U373 cells when they are cultured on laminin, which is a pro-adhesive extracellular matrix component ubiquitously secreted by glioma cells. Our data thus strongly suggest that, in addition to gastrin, neurotensin is a neuropeptide capable of modulating tumour astrocyte migration into the brain parenchyma.
星形细胞瘤因其显著的弥漫性侵袭脑实质的能力而与预后不良相关。包括胃泌素在内的多种神经肽能够调节肿瘤星形胶质细胞的迁移。虽然神经降压素已被证明会影响胶质瘤细胞的增殖以及大量其他细胞类型的迁移能力，但其在胶质瘤细胞迁移中的作用从未被研究过。因此，神经降压素诱导的人U373胶质母细胞瘤细胞运动特征的改变构成了本研究的主题。我们证明，至少就其mRNA而言，神经降压素受体的三种亚型（NTR1、NTR2和NTR3）在U373胶质母细胞瘤细胞中表达。用10 nM神经降压素处理U373肿瘤细胞显著改变了这些细胞的形态模式，并深刻改变了它们肌动蛋白细胞骨架的组织。下拉实验表明，神经降压素诱导U373细胞中Rac1和Cdc42的激活，但不诱导RhoA的激活。划痕实验证明，神经降压素（0.1和10 nM）非常显著地抑制了在无血清条件下培养的U373细胞的伤口愈合。此外，定量相差视频显微镜分析表明，当U373胶质母细胞瘤细胞在塑料上培养时，神经降压素会降低其运动水平。与之形成鲜明对比的是，当U373细胞在层粘连蛋白上培养时，神经降压素会刺激其运动，层粘连蛋白是一种由胶质瘤细胞普遍分泌的促黏附细胞外基质成分。因此，我们的数据强烈表明，除了胃泌素之外，神经降压素也是一种能够调节肿瘤星形胶质细胞向脑实质迁移的神经肽。
