title: Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma.
abstract: 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-κB, 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 productionin vitroandin vivo. Moreover, we demonstrated that tumor neutrophils, via HGF/c-Met interaction, actively enhanced the metastasis of malignant cellsin vitroandin 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.
authors.affiliation: Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Anping
authors.initials: A
authors.lastname: Peng
authors.affiliation: Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, P.R. China.
authors.forename: Dai-Chao
authors.initials: DC
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, P.R. China.
authors.forename: Jun-Cheng
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University , Guangzhou, P.R. China.
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Haibiao
authors.initials: H
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, P.R. China.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
authors.affiliation: Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou, P.R. China.
authors.forename: Pei-Feng
authors.initials: PF
authors.lastname: Ke
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center , Guangzhou, P.R. China.
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Lao
keywords: HCC; c-Met; hepatocyte growth factor; metastasis; tumor neutrophils