Annals of Surgical Oncology

, Volume 21, Issue 3, pp 1031–1037 | Cite as

Tumor-Associated Macrophages Promote Oral Cancer Progression Through Activation of the Axl Signaling Pathway

  • Chien-Hsing Lee
  • Shyun-Yeu Liu
  • Kuo-Chou Chou
  • Chi-Tai Yeh
  • Shine-Gwo Shiah
  • Ren-Yeong Huang
  • Jen-Chan Cheng
  • Ching-Yu Yen
  • Yi-Shing Shieh
Translational Research and Biomarkers

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.

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Copyright information

© Society of Surgical Oncology 2013

Authors and Affiliations

  • Chien-Hsing Lee
    • 1
  • Shyun-Yeu Liu
    • 2
  • Kuo-Chou Chou
    • 3
  • Chi-Tai Yeh
    • 4
  • Shine-Gwo Shiah
    • 5
  • Ren-Yeong Huang
    • 3
  • Jen-Chan Cheng
    • 6
  • Ching-Yu Yen
    • 2
  • Yi-Shing Shieh
    • 3
    • 7
  1. 1.Department of Internal Medicine,Tri-Service General HospitalNational Defense Medical CenterTaipeiTaiwan
  2. 2.Department of Oral and Maxillofacial SurgeryChi Mei Medical CenterTainanTaiwan
  3. 3.Department of Dentistry, Tri-Service General HospitalNational Defense Medical CenterTaipeiTaiwan
  4. 4.Graduate Institute of Clinical MedicineTaipei Medical UniversityTaipeiTaiwan
  5. 5.Institute of Cancer ResearchNational Health Research InstitutesMiaoliTaiwan
  6. 6.Oral Maxillofacial Surgery DepartmentCardinal Tien Ken-Sin HospitalNew TaipeiTaiwan
  7. 7.School of DentistryNational Defense Medical CenterTaipeiTaiwan

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