Microenvironmental stiffness enhances glioma cell proliferation by stimulating epidermal growth factor receptor signaling.
Microenvironmental stiffness enhances glioma cell proliferation by stimulating epidermal growth factor receptor signaling.
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DOI：
10.1371/journal.pone.0101771
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Umesh V;Rape AD;Ulrich TA;Kumar S
脑胶质母细胞瘤(GBM)是一种侵袭性强、致命性强的脑肿瘤，与表皮生长因子受体(EGFR)通路关键成员的深层组织硬化和基因组损伤有关。我们实验室以前的研究表明，增加培养的微环境硬度可以强烈地增强胶质瘤细胞与肿瘤进展相关的行为，包括增殖，但目前尚不清楚刚性和EGFR是否通过共同或独立的信号机制来调节增殖。在这里，我们测试了微环境僵硬通过改变EGFR依赖的信号来调节GBM肿瘤细胞的细胞周期进展和增殖的假设。我们首先进行了无偏反相蛋白质阵列筛选，结果显示，僵硬调节与增殖相关的广泛信号的表达和磷酸化，包括EGFR途径的成员。我们随后发现，在逐渐变硬的培养底物上培养人基底细胞瘤细胞既显著促进了增殖，又促进了细胞周期的G1/S检查点的通过，这与表皮生长因子受体依赖的过程一致。Western blotts结果显示，随着微环境硬度的增加，EGFR及其下游效应蛋白Akt的表达和磷酸化程度增强。药理功能丧失研究表明，抑制EGFR、Akt或PI3激酶可强烈钝化细胞增殖的僵硬敏感性。最后，我们观察到刚性强烈地调节了EGFR的聚集，磷酸化的EGFR凝聚成坚硬底物上的纽蛋白阳性的焦点粘连，并随着微环境刚性下降到生理水平而分散。我们的发现共同支持一种模型，在该模型中，组织硬化通过空间和生化放大EGFR信号来促进GBM的增殖。
The aggressive and rapidly lethal brain tumor glioblastoma (GBM) is associated with profound tissue stiffening and genomic lesions in key members of the epidermal growth factor receptor (EGFR) pathway. Previous studies from our laboratory have shown that increasing microenvironmental stiffness in culture can strongly enhance glioma cell behaviors relevant to tumor progression, including proliferation, yet it has remained unclear whether stiffness and EGFR regulate proliferation through common or independent signaling mechanisms. Here we test the hypothesis that microenvironmental stiffness regulates cell cycle progression and proliferation in GBM tumor cells by altering EGFR-dependent signaling. We began by performing an unbiased reverse phase protein array screen, which revealed that stiffness modulates expression and phosphorylation of a broad range of signals relevant to proliferation, including members of the EGFR pathway. We subsequently found that culturing human GBM tumor cells on progressively stiffer culture substrates both dramatically increases proliferation and facilitates passage through the G1/S checkpoint of the cell cycle, consistent with an EGFR-dependent process. Western Blots showed that increasing microenvironmental stiffness enhances the expression and phosphorylation of EGFR and its downstream effector Akt. Pharmacological loss-of-function studies revealed that the stiffness-sensitivity of proliferation is strongly blunted by inhibition of EGFR, Akt, or PI3 kinase. Finally, we observed that stiffness strongly regulates EGFR clustering, with phosphorylated EGFR condensing into vinculin-positive focal adhesions on stiff substrates and dispersing as microenvironmental stiffness falls to physiological levels. Our findings collectively support a model in which tissue stiffening promotes GBM proliferation by spatially and biochemically amplifying EGFR signaling.
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影响因子：
5.7
作者：
Golubovskaya VM;Huang G;Ho B;Yemma M;Morrison CD;Lee J;Eliceiri BP;Cance WG
通讯作者：
Cance WG
DOI：
10.1083/jcb.200504124
发表时间：
2005-11-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Benlimame N;He Q;Jie S;Xiao D;Xu YJ;Loignon M;Schlaepfer DD;Alaoui-Jamali MA
通讯作者：
Alaoui-Jamali MA
影响因子：
4.1
作者：
Halatsch, ME;Gehrke, EE;Buchfelder, M
通讯作者：
Buchfelder, M
影响因子：
14
作者：
Ananthanarayanan, Badriprasad;Kim, Yushan;Kumar, Sanjay
通讯作者：
Kumar, Sanjay
影响因子：
11.2
作者：
Lathia, Justin D.;Li, Meizhang;Hall, Peter E.;Gallagher, Joseph;Hale, James S.;Wu, Qiulian;Venere, Monica;Levy, Emily;Rani, M. R. Sandhya;Huang, Ping;Bae, Eunnyung;Selfridge, Julia;Cheng, Lin;Guvenc, Hacer;McLendon, Roger E.;Nakano, Ichiro;Sloan, Andrew E.;Phillips, Heidi S.;Lai, Albert;Gladson, Candece L.;Bredel, Markus;Bao, Shideng;Hjelmeland, Anita B.;Rich, Jeremy N.
通讯作者：
Rich, Jeremy N.