• met
• neutrofili antitumorali
• anti-tumor neutrophils

HGF-mediated activation of Met fosters cancer cell proliferation, survival,
motility, invasion and angiogenesis. Given the important role of Met signaling in
cancer, several Met inhibitors are currently evaluated in clinical trials. Since
little if any is known about the role of Met in the tumor stroma, here we
investigated if and how gene inactivation of Met in endothelial and
hematopoietic cells influences tumor progression, disclosing possible modes of
resistance to Met inhibitors in anti-tumor therapies. By using different tumor
models, we found that Met has a dispensable role in the endothelial cells during
tumor progression, while the genetic deletion of its catalytic domain in the
hematopoitic lineage fosters tumor growth, resulting in increased tumor weight
and metastatic dissemination. This correlates with a reduction of tumor infiltrating
neutrophils upon Met deletion. Moreover, in two different models of
inflammation, we found that Met is required for neutrophil recruitment at the
inflammatory sites. In particular, we found that cell membrane bound TNF-α on
the pro-inflammatory endothelium (as it happens in cancer) strongly enhanced
Met expression in neutrophils; furthermore, HGF increased the firm adhesion of
neutrophils to an activated endothelium in a Met-mediated manner and also their
transmigration in vitro and in vivo. Due to the importance of inflammatory cell
recruitment and polarization during tumor progression, our finding shed light on
the « Achille heel » of anti-Met targeted therapy and suggest new perspectives for
their improvements.