MET is required for the recruitment of anti-tumoural neutrophils

Nature. 2015 Jun 18;522(7556):349-53. doi: 10.1038/nature14407. Epub 2015 May 18.

Abstract

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacology*
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Deletion
  • Hepatocyte Growth Factor
  • Humans
  • Inflammation / immunology
  • Inflammation / pathology
  • Male
  • Mice
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Nitric Oxide / metabolism
  • 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*
  • Solubility
  • Transendothelial and Transepithelial Migration
  • Tumor Necrosis Factor-alpha / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met