Journal Article

MET is required for the recruitment of anti-tumoural neutrophils

Casazza, Andrea, Costa, Sandra, Thompson, A. A. Roger, Serneels, Jens, Wauters, Els, Di Matteo, Mario, Walmsley, Sarah, Di Conza, Giusy, Finisguerra, Veronica, Mazzone, Massimiliano, Prenen, Hans, Granot, Zvi

2015

Overview

Whether neutrophils exert an anti- or pro-tumorigenic function has remained controversial; now, expression of the receptor molecule MET in neutrophils is shown to be required for their ability to restrict tumour growth in several mouse cancer models, with potential implications for human cancer therapy. Anti-tumour function for MET Whether neutrophils exert and anti- or pro-tumorigenic function has remained controversial. Massimiliano Mazzone and colleagues now show in several mouse models of cancer that expression of the receptor molecule MET in neutrophils is required for their ability to restrict tumour growth. MET expression in neutrophils is triggered by inflammatory signals, which can also be tumour-derived. MET activity is required for neutrophils to cross an activated endothelium to reach a tumour and to kill cancer cells. MET has been shown to be a therapeutic target in cancer cells which express MET, therefore the findings suggest that any beneficial effect is countered by inhibition of the anti-tumour neutrophil response, and the authors indeed demonstrate this in their mouse model. These findings are of relevance to therapeutic decisions based on anti-MET drugs, where it may be useful to monitor effects of the treatment in tumours showing a neutrophil response. Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours 1 , 2 , 3 , 4 , which rely on the constitutive engagement of this pathway for their growth and survival 1 , 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 characterized 6 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/106 / 13/107 / 13/109 / 13/31 / 13/51 / 13/89 / 13/95 / 14/63 / 38/77 / 38/90 / 42/41 / 42/44 / 631/67/327 / 64/110 / 64/60 / 82/1 / 82/29 / 82/80 / 96/2 / 96/21 / Aged / Animals / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacology / Cancer cells / Ciências Médicas / Disease Models, Animal / Disease Progression / Female / Gene Deletion / Health aspects / Hematopoietic growth factors / Hepatocyte Growth Factor / Humanities and Social Sciences / Humans / Inflammation - immunology / Inflammation - pathology / letter / Male / Medicina Básica / Mice / Middle Aged / multidisciplinary / Neoplasm Metastasis / Neoplasms - drug therapy / Neoplasms - immunology / Neoplasms - metabolism / Neoplasms - pathology / Neutrophils / Neutrophils - drug effects / Neutrophils - immunology / Neutrophils - metabolism / Nitric Oxide - metabolism / Physiological aspects / Proto-Oncogene Mas / Proto-Oncogene Proteins c-met - antagonists & inhibitors / Proto-Oncogene Proteins c-met - deficiency / Proto-Oncogene Proteins c-met - genetics / Proto-Oncogene Proteins c-met - metabolism / Science / Solubility / Transendothelial and Transepithelial Migration / Tumor Necrosis Factor-alpha - metabolism / Xenograft Model Antitumor Assays