Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer.
Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer.
复制标题
DOI：
10.1186/s12943-015-0310-8
复制
发表时间：
2015-02-20
期刊：
影响因子：
37.3
通讯作者：
O'Byrne KJ
中科院分区：
文献类型：
--
作者：
Barr MP;Gray SG;Gately K;Hams E;Fallon PG;Davies AM;Richard DJ;Pidgeon GP;O'Byrne KJ
VEGF通路已成为肺癌的重要治疗靶点，其中VEGF长期以来被确定为由许多类型的肿瘤表达的有效促血管生成生长因子。虽然贝伐珠单抗（安维汀）已被证明在增加NSCLC患者的客观肿瘤缓解率和延长进展和总生存期方面是成功的，但生存期获益相对较短，大多数患者最终复发。目前单独使用酪氨酸激酶抑制剂和与化疗联合使用的情况并不令人满意，这突出了对新靶向治疗的迫切需求。在这项研究中，我们研究了VEGF介导的NSCLC细胞存活的机制以及Neuropilin受体在这一过程中的作用。筛选NSCLC细胞的VEGF及其受体表达。检测重组VEGF及其阻断剂对肺癌细胞增殖和细胞周期的影响。高含量分析和共聚焦显微镜检查Akt和Erk 1/2蛋白的磷酸化。还评估了沉默VEGF对细胞增殖和存活信号传导的影响。产生神经纤毛蛋白-1稳定转染的细胞系。除了pAkt和pErk 1/2信号转导的细胞生长特性进行了研究，在响应VEGF和其封锁。在皮下注射NP 1过表达细胞后，在裸鼠中进行肿瘤生长研究。用抗VEGF和抗VEGFR-2抗体或针对VEGF、NP 1和NP 2的siRNA抑制VEGF途径导致NP 1阳性肿瘤细胞系的生长抑制，其与PI 3 K和MAPK激酶信号转导的下调相关。NP 1稳定转染NP 1阴性的细胞在体外诱导增殖，外源性VEGF进一步增强。在体内，与对照相比，NP 1过表达细胞显著增加异种移植物中的肿瘤生长。我们的数据表明，VEGF是NSCLC信号传导中的自分泌生长因子，至少部分通过NP 1。靶向这种VEGF受体可能提供作为一种新的治疗方法的潜力，也支持评估NP 1作为生物标志物的作用，预测在临床竞技场中对VEGF和VEGF靶向治疗的敏感性或耐药性。本文的在线版本（doi：10.1186/s12943-015-0310-8）包含补充材料，可供授权用户使用。
The VEGF pathway has become an important therapeutic target in lung cancer, where VEGF has long been established as a potent pro-angiogenic growth factor expressed by many types of tumors. While Bevacizumab (Avastin) has proven successful in increasing the objective tumor response rate and in prolonging progression and overall survival in patients with NSCLC, the survival benefit is however relatively short and the majority of patients eventually relapse. The current use of tyrosine kinase inhibitors alone and in combination with chemotherapy has been underwhelming, highlighting an urgent need for new targeted therapies. In this study, we examined the mechanisms of VEGF-mediated survival in NSCLC cells and the role of the Neuropilin receptors in this process. NSCLC cells were screened for expression of VEGF and its receptors. The effects of recombinant VEGF and its blockade on lung tumor cell proliferation and cell cycle were examined. Phosphorylation of Akt and Erk1/2 proteins was examined by high content analysis and confocal microscopy. The effects of silencing VEGF on cell proliferation and survival signaling were also assessed. A Neuropilin-1 stable-transfected cell line was generated. Cell growth characteristics in addition to pAkt and pErk1/2 signaling were studied in response to VEGF and its blockade. Tumor growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells. Inhibition of the VEGF pathway with anti-VEGF and anti-VEGFR-2 antibodies or siRNA to VEGF, NP1 and NP2 resulted in growth inhibition of NP1 positive tumor cell lines associated with down-regulation of PI3K and MAPK kinase signaling. Stable transfection of NP1 negative cells with NP1 induced proliferation in vitro, which was further enhanced by exogenous VEGF. In vivo, NP1 over-expressing cells significantly increased tumor growth in xenografts compared to controls. Our data demonstrate that VEGF is an autocrine growth factor in NSCLC signaling, at least in part, through NP1. Targeting this VEGF receptor may offer potential as a novel therapeutic approach and also support the evaluation of the role of NP1 as a biomarker predicting sensitivity or resistance to VEGF and VEGFR-targeted therapies in the clinical arena. The online version of this article (doi:10.1186/s12943-015-0310-8) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.8
作者：
Pan, Qi;Chathery, Yvan;Watts, Ryan J.
通讯作者：
Watts, Ryan J.
影响因子：
158.5
作者：
Sandler, Alan;Gray, Robert;Johnson, David H.
通讯作者：
Johnson, David H.
影响因子：
11.2
作者：
Cao Y;Wang L;Nandy D;Zhang Y;Basu A;Radisky D;Mukhopadhyay D
通讯作者：
Mukhopadhyay D
DOI：
10.1084/jem.20111424
发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hamerlik P;Lathia JD;Rasmussen R;Wu Q;Bartkova J;Lee M;Moudry P;Bartek J Jr;Fischer W;Lukas J;Rich JN;Bartek J
通讯作者：
Bartek J
影响因子：
4.8
作者：
Gluzman-Poltorak, Z;Cohen, T;Neufeld, G
通讯作者：
Neufeld, G