Brockmann Marc-Alexander, Ulbricht Ulrike, Grüner Katrin, Fillbrandt Regina, Westphal Manfred, Lamszus Katrin
Hans-Dietrich Herrmann Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Neurosurgery. 2003 Jun;52(6):1391-9; discussion 1399. doi: 10.1227/01.neu.0000064806.87785.ab.
Glioma cell migration is determined by a complex interplay between soluble motogens and extracellular matrix components. Several growth factors are thought to be involved in glioma cell migration; however, little is known about their motogenic potency relative to one another.
Using modified Boyden chamber assays, we compared the chemotactic effects of scatter factor/hepatocyte growth factor (SF/HGF), transforming growth factor (TGF)-alpha, TGF-beta1, TGF-beta2, epidermal growth factor (EGF), fibroblast growth factor (FGF)-1, FGF-2, insulin-like growth factor (IGF)-1, IGF-2, platelet-derived growth factor (PDGF)-AA, PDGF-BB, vascular endothelial growth factor (VEGF), pleiotrophin (PTN), and midkine (MK) in concentrations ranging from 1 pmol/L to 50 nmol/L on three different human glioblastoma cell lines. Checkerboard analyses distinguished between chemotaxis and chemokinesis. We further investigated the motogenic effects on human cerebral microvascular endothelial cells and analyzed receptor expression profiles.
SF/HGF was the most potent chemotactic factor for all three glioblastoma cell lines, inducing up to 33-fold stimulation of migration. TGF-alpha showed the second strongest effect (up to 17-fold stimulation), and FGF-1 was also chemotactic for all three glioblastoma cell lines analyzed (maximal 4-fold effect). EGF, FGF-2, IGF-1, IGF-2, TGF-beta1, and TGF-beta2 were chemotactic for one or two of the cell lines (2- to 4-fold effects), whereas PDGF-AA, PDGF-BB, VEGF, PTN, and MK had no effect. In contrast, the most potent stimulators of cerebral microvascular endothelial cell migration were PDGF-AA (4-fold) and PDGF-BB (6-fold).
The expression levels of SF/HGF and TGF-alpha as well as their respective receptors, MET and EGFR, are known to correlate with glioma malignancy grade. The particularly strong motogenic effects of these two growth factors suggest that they could be promising targets for an antimigratory component of glioma therapy, at least in comparison with the 12 other factors that were analyzed.
胶质瘤细胞迁移由可溶性促细胞运动因子与细胞外基质成分之间复杂的相互作用决定。几种生长因子被认为参与胶质瘤细胞迁移；然而，它们彼此之间的促细胞运动能力知之甚少。
使用改良的博伊登小室试验，我们比较了散射因子/肝细胞生长因子（SF/HGF）、转化生长因子（TGF）-α、TGF-β1、TGF-β2、表皮生长因子（EGF）、成纤维细胞生长因子（FGF）-1、FGF-2、胰岛素样生长因子（IGF）-1、IGF-2、血小板衍生生长因子（PDGF）-AA、PDGF-BB、血管内皮生长因子（VEGF）、多效生长因子（PTN）和中期因子（MK）在1 pmol/L至50 nmol/L浓度范围内对三种不同人类胶质母细胞瘤细胞系的趋化作用。棋盘分析区分趋化作用和趋化运动。我们进一步研究了对人脑血管内皮细胞的促细胞运动作用并分析了受体表达谱。
SF/HGF是所有三种胶质母细胞瘤细胞系中最有效的趋化因子，可诱导高达33倍的迁移刺激。TGF-α显示出第二强的作用（高达17倍刺激），并且FGF-1对所有三种分析的胶质母细胞瘤细胞系也具有趋化作用（最大4倍作用）。EGF、FGF-2、IGF-1、IGF-2、TGF-β1和TGF-β2对其中一或两种细胞系具有趋化作用（2至4倍作用），而PDGF-AA、PDGF-BB、VEGF、PTN和MK没有作用。相比之下，脑血管内皮细胞迁移的最有效刺激物是PDGF-AA（4倍）和PDGF-BB（6倍）。
已知SF/HGF和TGF-α及其各自受体MET和表皮生长因子受体（EGFR）的表达水平与胶质瘤恶性程度相关。这两种生长因子特别强的促细胞运动作用表明，至少与分析的其他12种因子相比，它们可能是胶质瘤治疗抗迁移成分的有前景的靶点。
