Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells
Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells
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DOI：
10.1038/sj.onc.1203783
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发表时间：
2000-08-31
期刊：
影响因子：
8
通讯作者：
Weller, M
中科院分区：
文献类型：
--
作者：
Roth, W;Wild-Bode, C;Weller, M
细胞对多种促凋亡刺激的抵抗和移行肿瘤细胞对周围脑组织的侵袭是人类恶性胶质瘤有效治疗的主要障碍。在此，我们报道了Wnt家族胚胎分化基因在体外和VILL中调节恶性胶质瘤细胞的生长，并在体外抑制细胞迁移。SFRPs(SFRPs)是一种与Wnt结合并干扰Wnt信号转导的可溶性蛋白。我们发现SFRP-1和SFRP-2是由大多数长期和体外恶性胶质瘤细胞系产生的。异位表达sFRPs的胶质瘤细胞表现出更强的克隆性和对血清饥饿的抵抗力。相反，sFRPs不能调节细胞毒性细胞因子、CD95(Fas/APO-1)配体(CD95L)或APO2配体/肿瘤坏死因子相关的凋亡诱导配体(Apo2L/TRAIL)或各种细胞毒性药物诱导的胶质瘤细胞的凋亡敏感性。SFRP-2对脑胶质瘤裸鼠移植瘤生长有明显的促进作用。相反，sFRPs的增强表达在体外抑制了胶质瘤细胞的运动。SFRP对胶质瘤细胞的作用伴随着基质金属蛋白酶-2(MMP2)表达和活性的降低以及β-连环素酪氨酸磷酸化的降低。因此，sFRPs在非支持性条件下促进存活，并抑制胶质瘤细胞的迁移。我们认为，这些细胞过程的调节涉及到基质金属蛋白酶-2的表达和β-连环素的酪氨酸磷酸化。这些数据支持Wnt信号的功能以及sFRPs在人脑胶质瘤生物学中的调节作用。
Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in ville and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2: and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas.