Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling.
Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling.
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在胶质母细胞瘤（GBM）中，EGF受体（EGFR）和Src家族激酶（SFKs）促成了侵袭性表型。EGFR可以作为治疗的靶标；然而，对egfr靶向药物如厄洛替尼和吉非替尼的耐药性发展迅速。在许多GBMs中，EGFR的一种截断形式（EGFRvIII）被表达。尽管EGFRvIII具有组成性活性并促进癌症进展，但与egf连接的野生型EGFR相比，其活性减弱，这表明EGFRvIII可能与癌细胞中的其他信号受体一起作用，诱导侵袭性表型。在本研究中，我们证明了在表达egfrviii的GBM细胞中，尿激酶受体（uPAR）作为SFKs的主要激活剂，在体外和体内控制EGFR下游靶点如p130Cas和Tyr-845的磷酸化。当EGFRvIII在GBM细胞中的表达被中和时，无论是通过遗传还是用吉非替尼处理细胞，矛盾的是，细胞表现出增加的细胞迁移。细胞迁移的增加可以解释为尿激酶型纤溶酶原激活物表达的代偿性增加，该激活物激活upar依赖性细胞信号传导。由于uPAR信号系统的激活，在缺乏EGFRvIII的情况下能够在体内生长的GBM细胞也表现出增加的细胞迁移。由EGFR的遗传或药物靶向诱导的GBM细胞迁移增加被达沙替尼阻断，突出了sfk在upar促进的细胞迁移中的核心作用。这些结果表明，在靶向治疗的GBM细胞中，upar依赖性细胞信号的代偿性激活可能通过促进细胞迁移而对疾病进程产生不利影响，这可能与肿瘤进展有关。
In glioblastoma (GBM), the EGF receptor (EGFR) and Src family kinases (SFKs) contribute to an aggressive phenotype. EGFR may be targeted therapeutically; however, resistance to EGFR-targeting drugs such as Erlotinib and Gefitinib develops quickly. In many GBMs, a truncated form of the EGFR (EGFRvIII) is expressed. Although EGFRvIII is constitutively active and promotes cancer progression, its activity is attenuated compared with EGF-ligated wild-type EGFR, suggesting that EGFRvIII may function together with other signaling receptors in cancer cells to induce an aggressive phenotype. In this study, we demonstrate that in EGFRvIII-expressing GBM cells, the urokinase receptor (uPAR) functions as a major activator of SFKs, controlling phosphorylation of downstream targets such as p130Cas and Tyr-845 in the EGFR in vitro and in vivo. When EGFRvIII expression in GBM cells was neutralized, either genetically or by treating the cells with Gefitinib, paradoxically, the cells demonstrated increased cell migration. The increase in cell migration was explained by a compensatory increase in expression of urokinase-type plasminogen activator, which activates uPAR-dependent cell-signaling. GBM cells that were selected for their ability to grow in vivo in the absence of EGFRvIII also demonstrated increased cell migration, due to activation of the uPAR signaling system. The increase in GBM cell migration, induced by genetic or pharmacologic targeting of the EGFR, was blocked by Dasatinib, highlighting the central role of SFKs in uPAR-promoted cell migration. These results suggest that compensatory activation of uPAR-dependent cell-signaling, in GBM cells treated with targeted therapeutics, may adversely affect the course of the disease by promoting cell migration, which may be associated with tumor progression.
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影响因子：
21.3
作者：
Felsenfeld, DP;Schwartzberg, PL;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
10.5
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
通讯作者：
Furnari, Frank
DOI：
10.1073/pnas.1113416108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Hu, Jingjing;Jo, Minji;Gonias, Steven L.
通讯作者：
Gonias, Steven L.
影响因子：
6.7
作者：
Alfano, D;Franco, P;Stoppelli, MP
通讯作者：
Stoppelli, MP
影响因子：
46.9
作者：
Du, Jinyan;Bernasconi, Paula;Clauser, Karl R.;Mani, D. R.;Finn, Stephen P.;Beroukhim, Rameen;Burns, Melissa;Julian, Bina;Peng, Xiao P.;Hieronymus, Haley;Maglathlin, Rebecca L.;Lewis, Timothy A.;Liau, Linda M.;Nghiemphu, Phioanh;Mellinghoff, Ingo K.;Louis, David N.;Loda, Massimo;Carr, Steven A.;Kung, Andrew L.;Golub, Todd R.
通讯作者：
Golub, Todd R.