MET is required for the recruitment of anti-tumoural neutrophils.
MET is required for the recruitment of anti-tumoural neutrophils.
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DOI：
10.1038/nature14407
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发表时间：
2015-06-18
期刊：
影响因子：
64.8
通讯作者：
Mazzone M
中科院分区：
文献类型：
--
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
MET原癌基因的突变或扩增参与了几种肿瘤的发病机制，这些肿瘤的生长和存活依赖于该途径的组成性参与。然而，MET不仅由癌细胞表达，而且还由肿瘤相关基质细胞表达，尽管其在该隔室中的确切作用还没有得到很好的表征。在这里，我们表明，MET是所需的中性粒细胞的化学吸引力和细胞毒性反应，其配体肝细胞生长因子。中性粒细胞中的Met缺失促进肿瘤生长和转移。这种表型与原发肿瘤和转移部位的中性粒细胞浸润减少相关。同样，Met对于结肠炎、皮疹或腹膜炎期间的中性粒细胞渗出是必需的。从机制上讲，Met是由小鼠和人中性粒细胞中的肿瘤源性TNF-α或其他炎症刺激诱导的。这种诱导有助于中性粒细胞穿过活化的内皮和HGF刺激后的iNOS产生。因此，由嗜中性粒细胞释放的HGF/MET依赖性一氧化氮促进癌细胞杀伤，从而减轻肿瘤生长和转移。在全身给予MET激酶抑制剂后，我们证明了MET靶向癌细胞的治疗益处部分地被中性粒细胞中MET阻断引起的促肿瘤效应抵消。我们的工作确定了MET在中性粒细胞中的前所未有的作用，表明了MET靶向治疗癌症的潜在“阿喀琉斯之踵”，并支持在某些炎症性疾病中评估抗MET药物的基本原理。
Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. 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 characterized. Here, we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand HGF. Met deletion in neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both primary tumour and metastatic site. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived TNF-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and iNOS production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. Following 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 rising 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.