Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis.
Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis.
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内皮δ样4（DLL4）促进肾细胞癌血行转移
DOI：
10.18632/oncotarget.1827
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发表时间：
2014-05-30
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Huang QB;Ma X;Li HZ;Ai Q;Liu SW;Zhang Y;Gao Y;Fan Y;Ni D;Wang BJ;Zhang X
Notch配体Delta-like 4（DLL 4）在肿瘤血管生成中起重要作用，这是肿瘤侵袭和转移所必需的。在这里，我们发现DLL 4在内皮细胞中升高，并且Notch信号在肾细胞癌（RCC）中被激活。外源性DLL 4通过激活细胞间Notch信号通路诱导肾癌细胞迁移和侵袭。重要的是，DLL 4/Notch/Hey 1/MMP 9级联反应在转移中将内皮细胞连接到癌细胞。Hey 1基因的敲除降低了MMP 9的表达，并减弱了肿瘤的侵袭。对120例肾细胞癌标本的临床研究表明，Hey 1和MMP 9的表达与DLL 4密度相关。单因素和多因素分析显示，肿瘤血行转移不仅与微血管密度有关，还与肿瘤大小和DLL 4密度有关。在4年的监测中，高水平的DLL 4密度与更高的发生转移的可能性和对靶向治疗的敏感性相关。我们的数据表明，RCC进展部分是由激活的DLL 4/Notch信号，内皮和细胞的相互作用引起的，这可以是治疗靶向的。
The Notch ligand Delta-like 4 (DLL4) plays an important role in tumor angiogenesis, which is required for tumor invasion and metastasis. Here we showed that DLL4 was elevated in endothelium and Notch signaling was activated in renal cell carcinoma (RCC). Exogenous DLL4 induced RCC cell migration and invasion by activating intercellular Notch signaling. Importantly, the DLL4/Notch/Hey1/MMP9 cascades connecting the endothelium to the cancer cells in metastasis were identified. Knockdown of Hey1 decreased expression of MMP9 and attenuated tumor invasion. The clinical investigation on 120 cases of RCC specimens indicated that expressions of Hey1 and MMP9 correlated with DLL4 density. Moreover, univariate and multivariate analyses showed that tumor hematogenous metastasis not only was depended on microvessel density but was also associated with tumor size and DLL4 density. During 4-year surveillance, high-level of DLL4 density was associated with a higher probability of developing metastasis and being sensitive to target therapies. Our data suggest that RCC progression is caused in part by activated DLL4/Notch signaling, interaction of endothelium and cells, which can be therapeutically targeted.
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影响因子：
11.2
作者：
Patel, NS;Li, JL;Harris, AL
通讯作者：
Harris, AL
影响因子：
11.2
作者：
Indraccolo, Stefano;Minuzzo, Sonia;Amadori, Alberto
通讯作者：
Amadori, Alberto
影响因子：
6.6
作者：
Kunkle, David A.;Crispen, Paul L.;Uzzo, Robert G.
通讯作者：
Uzzo, Robert G.
根据肿瘤大小，转移性肾细胞癌风险。
DOI：
10.1016/j.juro.2009.02.128
发表时间：
2009-07
期刊：
The Journal of urology
影响因子：
--
作者：
Thompson RH;Hill JR;Babayev Y;Cronin A;Kaag M;Kundu S;Bernstein M;Coleman J;Dalbagni G;Touijer K;Russo P
通讯作者：
Russo P
影响因子：
64.8
作者：
Hellstroem, Mats;Phng, Li-Kun;Betsholtz, Christer
通讯作者：
Betsholtz, Christer