title: Tumor-associated macrophages promote oral cancer progression through activation of the Axl signaling pathway.
abstract: BACKGROUND
  Recent studies suggest that tumor-associated macrophages (TAMs) promote tumor growth and metastasis. Our previous report demonstrated that Axl signaling promotes carcinogenesis and progression of oral squamous cell carcinoma (OSCC). This study aims to test the potential involvement of growth arrest-specific gene 6 (Gas6)/Axl signaling in the protumoral effect of TAMs.
  
  
  METHODS
  Co-culture experiments by incubation of OSCC cells (YD38 and OE) and macrophages (THP-1) were performed. The expression of Gas6/Axl and epithelial-mesenchymal transition (EMT) genes were examined in YD38 and OE cells. The effect of Gas6/Axl signaling on co-cultured cancer cells was further investigated by knocking down Axl expression and neutralizing Gas6. Axl and TAM distribution were analyzed by immunohistochemistry in OSCC tissues.
  
  
  RESULTS
  Activation of Axl signaling and increased expression of mesenchymal markers, along with increased invasion/migration ability of OSCC cells, was noted upon co-culture with THP-1. Neutralization of Gas6 in the co-culture system or knockdown of Axl in YD38 caused the co-culture effects to be diminished. Co-culture with THP-1 increased nuclear factor (NF)-κB nuclear translocation and transcription activity in YD38 cells. A significant association between the TAM count and expression of phosphorylated Axl (P = 0.004) was found in vivo cancer tissues.
  
  
  CONCLUSIONS
  TAMs play a protumor role in OSCC and likely promote tumor progression through activation of the Gas6/Axl-NF-κB signaling pathway. Therefore, Gas6/Axl and NF-κB signaling in OSCC cells may be a putative target for therapeutic intervention.
authors.affiliation: Department of Internal Medicine,Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chien-Hsing
authors.initials: CH
authors.lastname: Lee
authors.forename: Shyun-Yeu
authors.initials: SY
authors.lastname: Liu
authors.forename: Kuo-Chou
authors.initials: KC
authors.lastname: Chou
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Yeh
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
authors.forename: Ren-Yeong
authors.initials: RY
authors.lastname: Huang
authors.forename: Jen-Chan
authors.initials: JC
authors.lastname: Cheng
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Yen
authors.forename: Yi-Shing
authors.initials: YS
authors.lastname: Shieh
mesh_terms: D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human