TGF-β-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system
TGF-β-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system
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DOI：
10.1002/ijc.1330
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发表时间：
2001-07-15
影响因子：
6.4
通讯作者：
Gress, TM
中科院分区：
文献类型：
--
作者：
Ellenrieder, V;Hendler, SF;Gress, TM
在晚期上皮性肿瘤中，Tcf-β强烈促进局部肿瘤的进展，尽管其潜在的机制尚不清楚。在本研究中，我们证明了转化生长因子-β增加胰腺癌细胞系Pang-I和IMIM-PCI侵袭力的潜力。转化生长因子-β诱导的肿瘤细胞侵袭以时间依赖的方式发生，开始于12小时后，甚至在单独应用生长因子48小时后继续增加。在治疗后24小时应用中和抗体阻断分泌的转化生长因子-β1，可完全阻断转化生长因子-β对肿瘤细胞侵袭的持续作用。结合我们之前观察到的TCF-Beta1上调自身在两种细胞系中的表达，我们的数据表明TCF-Beta1以自分泌的方式维持肿瘤细胞的侵袭。Northern印迹杂交和酶谱检测显示，经转化生长因子-β处理的PANC-1和IMIM-PC1细胞的基质金属蛋白酶-2(MMP2)和尿激酶型纤溶酶原激活物(UPA)系统的表达和活性均显著上调。用基质金属蛋白酶抑制剂或uPA系统抑制剂处理可显著降低转化生长因子-β诱导的两种细胞系的侵袭力。相反，在缺失II型受体(MiaPaca2)或Smad4基因(IMIM-PC2和Capan-1)的细胞系中，基质金属蛋白酶-2和uPA的表达和活性以及肿瘤细胞的侵袭性都没有受到影响，在这些细胞系中，转化生长因子-β也不能自动诱导自身的表达。综上所述，我们的结果表明转化生长因子-β1是胰腺癌进展的强有力的促进剂。因此，转化生长因子-β以自分泌的方式诱导肿瘤细胞的侵袭，这种侵袭是由基质金属蛋白酶-2和uPA系统介导的。(C)2001年Wiley-Liss，Inc.
TCF-beta strongly promotes local tumor progression in advanced epithelial tumors, though the underlying mechanisms are poorly understood. In the present study, we demonstrate the potential of TGF-beta to increase the invasiveness of the pancreatic cancer cell lines PANG-I and IMIM-PCI, TGF-beta -induced tumor cell invasion occurred in a time-dependent manner, started after 12 hr and continued to increase even 48 hr after a single application of the growth factor. Blocking of secreted TGF-beta1 by application of neutralizing antibodies 24 hr after TGF-beta treatment completely prevented the sustained effects of TGF-beta on tumor cell invasion. Together with our previous observation that TCF-beta1 up-regulates its own expression in both cell lines, our data suggest that TCF-beta1 acts in an autocrine manner to maintain tumor cell invasion. As measured by Northern blot hybridization and zymography, TGF-beta treatment of PANC-1 and IMIM-PC1 cells resulted in strong up-regulation of expression and activity of both matrix metalloproteinase-2 (MMP-2) and the urokinase plasminogen activator (uPA) system. Treatment with MMP inhibitors or inhibitors of the uPA system caused significant reduction of TGF-beta -induced invasiveness in both cell lines. In contrast, expression and activity of MMP-2 and uPA as well as tumor cell invasiveness remained unaffected in cell lines with defects of the TGF-beta type II receptor (MiaPaca2) or the Smad4 gene (IMIM-PC2 and CAPAN-1), In these cell lines, TGF-beta also failed to auto-induce its own expression. In conclusion, our results suggest that TGF-beta1 Is a strong promotor of pancreatic cancer progression. TGF-beta thereby acts in an autocrine manner to induce tumor cell invasion, which is mediated by MMP-2 and the uPA system. (C) 2001 Wiley-Liss, Inc.