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Nature:靶向MET治癌——生物版“阿喀琉斯之踵”

来源:生物谷 2015-05-22 16:32

                                                                

2015年5月22日讯 /生物谷BIOON/ --近日,来自比利时的科学家在著名国际学术期刊nature在线发表了一项最新研究进展,他们发现肝细胞生长因子受体MET在中性粒细胞趋化以及发挥杀伤活性方面具有重要作用,但通过药物靶向MET治疗癌症的治疗效果可能因MET在中性粒细胞中的作用而部分抵消。
 
原癌基因MET的突变或异常表达与多种肿瘤的发生有关,同时MET信号途径的组成型激活对于肿瘤生长和存活具有重要作用。有研究发现MET不仅在癌细胞中表达,在肿瘤相关的间充质细胞中也存在表达,但MET表达在肿瘤相关的间充质细胞中究竟发挥什么作用仍不清楚。
 
在该项研究中,研究人员发现MET对于中性粒细胞应答干细胞生长因子,产生趋化行为以及发挥细胞毒性具有重要作用。在小鼠中性粒细胞中删除Met会促进肿瘤生长及转移,这一表型与原发肿瘤和肿瘤转移灶中中性粒细胞浸润下降具有相关性。同时,MET对于中性粒细胞在大肠炎,皮疹和腹膜炎等疾病中的渗出也是非常必要的。
 
随后,研究人员对其中的机制进行了深入探究,他们发现在小鼠和人类中性粒细胞中MET的表达会受到肿瘤来源的TNFα以及其他炎症刺激的诱导,而这种诱导作用对于中性粒细胞跨越活化的内皮细胞以及在肝细胞生长因子刺激下产生诱导型一氧化氮合酶都是有帮助的。因此,由中性粒细胞释放的HGF/MET依赖性一氧化氮能够促进癌细胞杀伤,抑制肿瘤生长和转移。研究人员又通过全身给药的方式给予小鼠MET激酶抑制剂,证明靶向癌细胞中MET的治疗获益会因阻断中性粒细胞MET的肿瘤杀伤作用而发生部分抵消。
 
综上所述,这项研究发现MET在中性粒细胞发挥肿瘤杀伤作用方面具有重要作用,同时提出利用靶向MET的方法治疗癌症可能会因MET在中性粒细胞中的作用而不能获得理想的治疗效果。(生物谷Bioon.com)
 
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MET is required for the recruitment of anti-tumoural neutrophils
 
Veronica Finisguerra,Giusy Di Conza,Mario Di Matteo,Jens Serneels,Sandra Costa,A. A. Roger Thompson,Els Wauters,Sarah Walmsley,Hans Prenen,Zvi Granot,Andrea Casazza & Massimiliano Mazzone
 
Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours1, 2, 3, 4, which rely on the constitutive engagement of this pathway for their growth and survival1, 5. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized6, 7, 8, 9, 10, 11. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.
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