Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma

Inflammation is a component of tumor progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumors, but their regulation and functions in neoplasia are not understood. Here, we showed, in detailed studies of c-Met molecule in 225 untreated patients with hepatocellular carcinoma (HCC), that high infiltration of neutrophils in HCC tissues determined malignant cell c-Met-associated clinical outcome of patients. High infiltration of neutrophils in HCCs determined malignant cell c-Met-associated clinical outcome of patients. Neutrophils were enriched predominantly in invading tumor edge of HCCs; the accumulated neutrophils were the major source of c-Met ligand HGF in HCCs. Exposure to HCC environments resulted in neutrophil activation and the following HGF production. Inhibiting the activities of Erk1/2, p38, and NF-B, but not the phosphorylation of AKT or JNK, successfully attenuated the neutrophil HGF production induced by HCC environments. Further investigation revealed that GM-CSF was an important determinant in malignant cell-elicited neutrophil HGF production in vitro and in vivo. Moreover, we demonstrated that tumor neutrophils, via HGF/c-Met interaction, actively enhanced the metastasis of malignant cells in vitro and in vivo. These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in tumor milieu, which reroutes the immune activation into a tumor-promoting direction.