title: Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma.
abstract: OBJECTIVE
  Neutrophils are common cells of the inflammatory infiltrate and are predominantly enriched in many cancers. We recently found that neutrophils are accumulated in human hepatocellular carcinoma (HCC), where they promote disease progression by releasing matrix metalloproteinase-9 (MMP9). The underlying mechanisms, however, that allow tumour microenvironments to educate neutrophils are largely unknown.
  
  
  METHODS
  Neutrophils were purified from HCC patients and healthy donors. Immunohistochemistry and immunoblotting were used for the evaluation of autophagy in neutrophils. The regulation and function of increased neutrophil autophagy were assessed by both in vitro and ex vivo studies.
  
  
  RESULTS
  Most neutrophils in HCC intratumoural regions, in contrast to those located in the paired non-tumoural areas and within tumour vessels, substantially expressed autophagy-specific protein LC3. Soluble factors derived from hepatoma, including hyaluronan fragments, triggered a considerable increase of functional LC3 and autophagosomes in neutrophils, but this was unrelated to the deactivation of mTOR signalling. Inhibiting the activation of Erk1/2, p38, and NF-κB signals could significantly attenuate such tumour-elicited autophagy. These neutrophils, undergoing autophagy, exhibited long-lived phenotypes with retained Mcl-1 and significantly more intact mitochondria as well as low cleaved caspase-3, which could be abolished by inhibiting the initiation of autophagy. Moreover, increased neutrophil autophagy also correlated with sustained production of pro-metastatic oncostatin M and MMP9 and advanced migration of cancer cells.
  
  
  CONCLUSIONS
  Increased autophagy in neutrophils may represent a novel mechanism that links the innate response to neoplastic progression in humans. Studying the mechanisms that selectively modulate neutrophil autophagy will provide a novel strategy for anti-cancer therapy.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Dong-Ping
authors.initials: DP
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Fang-Zhu
authors.initials: FZ
authors.lastname: Ouyang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China. Electronic address: kdming@mail.sysu.edu.cn.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China; State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China. Electronic address: zhenglm@mail.sysu.edu.cn.
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009504:Neutrophils / Q000648:ultrastructure*; D015398:Signal Transduction
keywords: Autophagy; Hepatocellular carcinoma; Neutrophil; Pro-tumourigenic properties; Survival