EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis.
EGFR wild-type amplification and activation promote invasion and development of glioblastoma independent of angiogenesis.
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DOI：
10.1007/s00401-013-1101-1
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发表时间：
2013-05
影响因子：
12.7
通讯作者：
Miletic H
中科院分区：
文献类型：
--
作者：
Talasila KM;Soentgerath A;Euskirchen P;Rosland GV;Wang J;Huszthy PC;Prestegarden L;Skaftnesmo KO;Sakariassen PØ;Eskilsson E;Stieber D;Keunen O;Brekka N;Moen I;Nigro JM;Vintermyr OK;Lund-Johansen M;Niclou S;Mørk SJ;Enger PO;Bjerkvig R;Miletic H
血管生成被认为是癌症进展的标志，并且已经假设实体瘤的生长依赖于血管生成。然而，目前，肿瘤细胞的侵袭可以在没有血管生成的情况下发生，这一现象在恶性脑肿瘤，如胶质母细胞瘤（GBMs）的浸润性生长中尤为明显。在这些肿瘤中，野生型（wt）或截短和组成型激活的表皮生长因子受体（EGFR）的扩增或过表达被认为是GBM发展中的重要事件，其中复杂的下游信号事件与肿瘤细胞侵袭、血管生成和增殖有关。在这里，我们表明，野生型EGFR的扩增，特别是激活，代表了非血管生成性侵袭性肿瘤生长的潜在机制。通过临床相关的人GBM异种移植模型，我们发现具有EGFR基因扩增和激活的肿瘤细胞可以独立于血管生成而弥漫性地浸润正常脑组织，西妥昔单抗对EGFR活性的短暂抑制可以抑制肿瘤的侵袭性生长。此外，稳定、长期的显性阴性EGFR表达可导致间充质向上皮样转变，并诱导血管源性肿瘤生长。人类GBM活检分析证实，EGFR激活与侵袭性/非血管生成性肿瘤生长相关。总之，我们的研究结果表明，野生型EGFR的激活可以促进侵袭和胶质母细胞瘤的发展，而不依赖于血管生成，而其活性的丧失会导致血管生成肿瘤的生长。本文的在线版本（doi:10.1007/s00401-013-1101-1）包含补充材料，可供授权用户使用。
Angiogenesis is regarded as a hallmark of cancer progression and it has been postulated that solid tumor growth depends on angiogenesis. At present, however, it is clear that tumor cell invasion can occur without angiogenesis, a phenomenon that is particularly evident by the infiltrative growth of malignant brain tumors, such as glioblastomas (GBMs). In these tumors, amplification or overexpression of wild-type (wt) or truncated and constitutively activated epidermal growth factor receptor (EGFR) are regarded as important events in GBM development, where the complex downstream signaling events have been implicated in tumor cell invasion, angiogenesis and proliferation. Here, we show that amplification and in particular activation of wild-type EGFR represents an underlying mechanism for non-angiogenic, invasive tumor growth. Using a clinically relevant human GBM xenograft model, we show that tumor cells with EGFR gene amplification and activation diffusely infiltrate normal brain tissue independent of angiogenesis and that transient inhibition of EGFR activity by cetuximab inhibits the invasive tumor growth. Moreover, stable, long-term expression of a dominant-negative EGFR leads to a mesenchymal to epithelial-like transition and induction of angiogenic tumor growth. Analysis of human GBM biopsies confirmed that EGFR activation correlated with invasive/non-angiogenic tumor growth. In conclusion, our results indicate that activation of wild-type EGFR promotes invasion and glioblastoma development independent of angiogenesis, whereas loss of its activity results in angiogenic tumor growth. The online version of this article (doi:10.1007/s00401-013-1101-1) contains supplementary material, which is available to authorized users.
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影响因子：
11.2
作者：
Folkins C;Shaked Y;Man S;Tang T;Lee CR;Zhu Z;Hoffman RM;Kerbel RS
通讯作者：
Kerbel RS
影响因子：
8
作者：
Bonavia, R.;Inda, M. M.;Vandenberg, S.;Cheng, S-Y;Nagane, M.;Hadwiger, P.;Tan, P.;Sah, D. W. Y.;Cavenee, W. K.;Furnari, F. B.
通讯作者：
Furnari, F. B.
影响因子：
10.3
作者：
Haas-Kogan, DA;Prados, MD;Stokoe, D
通讯作者：
Stokoe, D
影响因子：
7
作者：
Johnson, Hannah;Del Rosario, Amanda M.;White, Forest M.
通讯作者：
White, Forest M.
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth