Laminin alpha 2 enables glioblastoma stem cell growth.
Laminin alpha 2 enables glioblastoma stem cell growth.
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DOI：
10.1002/ana.23674
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发表时间：
2012-11
影响因子：
11.2
通讯作者：
Rich, Jeremy N.
中科院分区：
文献类型：
--
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.
胶质母细胞瘤（GBMs）是一种致命的癌症，其细胞结构与正常大脑相似。位于顶端的是GBM干细胞（GSCs），它们对常规治疗具有相对抗性。恶性肿瘤和GSCs自我更新的一个重要驱动因素是与邻近血管周围生态位的相互作用。细胞外基质（ECM）提示神经干/祖细胞生态位相互作用，我们的研究目的是阐明其组成及其在血管周围生态位中维持GSC的作用。我们询问人类肿瘤组织进行免疫荧光分析，并从肿瘤组织中提取GSC进行功能研究。生物信息学分析通过挖掘公开可用的数据库进行。我们发现层粘连蛋白ECM蛋白定位于血管周围的GBM生态位，并提示患者预后不良。为了确定层粘连蛋白的来源，我们对生态位内的细胞元件进行了表征，发现层粘连蛋白α链在非干细胞肿瘤细胞和肿瘤相关内皮细胞（ECs）中表达。靶向层粘连蛋白α2的RNA干扰抑制GSC生长和自我更新。在GSCs和ECs共培养研究中，ECs中层粘连蛋白α2的敲低导致肿瘤生长下降。我们的研究强调了非干细胞来源的层粘连蛋白近胞嘧啶信号的贡献。由于层粘连蛋白α2最近被确定为侵袭性室管膜瘤的分子标志物，我们提出脑血管ECM通过维持GSC隔室促进肿瘤恶性发展，不仅提供了分子指纹，而且还提供了可能的治疗靶点。
Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. An important driver of malignancy and self-renewal in GSCs are interactions with the adjacent perivascular niche. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche. We interrogated human tumor tissue for immunofluorescence analysis and derived GSC from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases. We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by non-stem tumor cells and tumor associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth. Our studies highlight the contribution of non-stem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment providing not only a molecular fingerprint but also a possible therapeutic target.
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胶质瘤干细胞增殖和肿瘤生长由一氧化氮合酶2促进。
影响因子：
64.5
作者：
Eyler CE;Wu Q;Yan K;MacSwords JM;Chandler-Militello D;Misuraca KL;Lathia JD;Forrester MT;Lee J;Stamler JS;Goldman SA;Bredel M;McLendon RE;Sloan AE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
4.6
作者：
Campos, LS;Leone, DP;ffrench-Constant, C
通讯作者：
ffrench-Constant, C
影响因子：
5.2
作者：
Hall, Peter E.;Lathia, Justin D.;Ffrench-Constant, Charles
通讯作者：
Ffrench-Constant, Charles
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
影响因子：
3
作者：
Al-Mayhani, Talal M. Fael;Ball, Siolian L. R.;Watts, Colin
通讯作者：
Watts, Colin