Increased numbers of
tumor-infiltrating neutrophils are linked to poorer outcome in patients with
adenocarcinoma of the
bronchioloalveolar carcinoma (BAC) subtype.
Hepatocyte growth factor (HGF) is a pleiotropic
cytokine operating through activation of the proto-oncogene c-met and is
a factor of poor prognosis in various
cancers. Reports that neutrophils produce HGF led us to investigate their participation in the aerogenous spread of
tumor cells and the prognosis of BAC, through the effect of HGF on c-met-expressing
tumor cells. Immunoreactive HGF was detected in bronchoalveolar lavage fluid (BALF) supernatants from 34 of 36 patients, whereas it was undetectable in BALF from healthy controls. The HGF thus detected was locally produced, because HGF
mRNA was expressed by the patients' fresh alveolar cells, and HGF
protein was detected in 24-h culture supernatants. In immunocytochemical studies of BALF cytospin preparations and
tumor specimens from the patients, neutrophils were always HGF-positive, whereas alveolar macrophages and
tumor cells gave inconsistent results. Alveolar neutrophil-derived HGFs induced significant, concentration-dependent migration of BAC-derived
tumor cells in vitro, and this effect was inhibited by anti-HGF
neutralizing antibodies.
Granulocyte-macrophage colony-stimulating factor and
tumor necrosis factor alpha (present in the lung tumor microenvironment) provoked HGF release from neutrophil intracellular stocks, and the capacity of blood neutrophils from BAC patients to produce HGF was unaltered. Immunochemical studies of c-met expression in BALF cytospin preparations and
tumor sections showed that most
HGF receptor-bearing cells were
tumor cells. High HGF levels in BALF supernatants were significantly associated with poorer outcome in patients with BAC and were an independent predictor of clinical outcome in multivariate analysis. Altogether, our results support the notion that BAC generates a local environment that attracts functionally normal neutrophils from peripheral blood and leads to neutrophil release of biologically active HGF on contact with
HGF receptor-expressing
tumor cells, thereby contributing to poorer patient outcome.