由于MET原癌基因与多种肿瘤的发病机制有关，它成为了在当前的数十个临床试验中测试的一些未来疗法的一个兴趣靶点。

    来自比利时VIB研究所、鲁汶大学(KU Leuven)的Veronica Finisguerra、Andrea Casazza、Max Mazzone和同事们现在揭示出，MET是招募抗肿瘤中性粒细胞的必要条件，其通过一种机制发挥作用促使杀死了癌细胞。

    这表明，阻断中性粒细胞MET所引起的促肿瘤效应，将会部分地抵消靶向癌细胞中MET的抗癌疗法的疗效。这些见解有可能会促使优化当前测试的一些基于MET抑制剂的治疗方法，相关论文发布在权威期刊《自然》(Nature)杂志上。

    比利时VIB研究所/鲁汶大学的Max Mazzone说：“这些研究发现非常的重要，因为它会影响当前有超过15家公司参与的一些临床试验中所采用的一类药物。我们的研究结果或许可以用来提高一些临床前试验和I期——III期临床试验中20多种药物的疗效。我们的研究工作发现了MET在中性粒细胞中一种前所未知的作用，指出了MET靶向癌症疗法的一个潜在的‘致命弱点’。”

    MET在肿瘤免疫中

    过去对于MET的表达以及在肿瘤免疫中的功能知之甚少。由于一些免疫细胞在抑制恶性细胞生长和扩散的同时，也能够促进肿瘤的生成和转移，因此这一功能非常的重要。研究人员证实在诸如皮疹、腹膜炎和癌症等病理生理炎症过程中TNF-α可以诱导MET。MET是中性粒细胞HGF依赖性迁移通过炎症组织血管壁的必要条件，在炎症组织中中性粒细胞发挥了抗微生物和抗肿瘤功能。

    从免疫学角度来看，这强调了要对非特异性免疫反应进行巧妙和精细的控制，这是防止损害健康组织，反过来将细胞毒性反应限制在炎症位点的必要条件。

    双重效应

    从治疗的角度看，它表明了MET抑制剂有可能会对肿瘤造成双重影响：一方面，对依赖于MET过度激活来实现生长和生存的癌细胞起作用，MET抑制剂将会促进细胞周期阻滞或细胞死亡;另一方面，对中性粒细胞起作用，它们将会严重削弱促炎症、抗肿瘤反应。

    比利时VIB研究所/鲁汶大学的Max Mazzone说：“这项研究工作表明，在一些抗MET药物临床试验中应该基于MET的表达和癌细胞自身的依赖性来招募患者，排除那些中性粒细胞高水平表达MET的患者。

    原文标题：MET is required for the recruitment of anti-tumoural neutrophils

    原文摘要：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.