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

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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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Acknowledgment

This work was supported by research Grants (No. NSC99-2314B-016-026-MY3, No. CMNDMC10106, No. MAB101-16, and No. TSGH-C101-007-012-S01), Taiwan.

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Authors and Affiliations

  1. Department of Internal Medicine,Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Chien-Hsing Lee MD, PhD

  2. Department of Oral and Maxillofacial Surgery, Chi Mei Medical Center, Tainan, Taiwan

    Shyun-Yeu Liu DDS & Ching-Yu Yen DDS

  3. Department of Dentistry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Kuo-Chou Chou DDS, Ren-Yeong Huang DDS, PhD & Yi-Shing Shieh DDS, PhD

  4. Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

    Chi-Tai Yeh PhD

  5. Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan

    Shine-Gwo Shiah PhD

  6. Oral Maxillofacial Surgery Department, Cardinal Tien Ken-Sin Hospital, New Taipei, Taiwan

    Jen-Chan Cheng DDS

  7. School of Dentistry, National Defense Medical Center, Taipei, Taiwan

    Yi-Shing Shieh DDS, PhD

Authors
  1. Chien-Hsing Lee MD, PhD
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  2. Shyun-Yeu Liu DDS
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  3. Kuo-Chou Chou DDS
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  4. Chi-Tai Yeh PhD
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  5. Shine-Gwo Shiah PhD
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  6. Ren-Yeong Huang DDS, PhD
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  7. Jen-Chan Cheng DDS
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  8. Ching-Yu Yen DDS
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  9. Yi-Shing Shieh DDS, PhD
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Corresponding author

Correspondence to Yi-Shing Shieh DDS, PhD.

Additional information

Chien-Hsing Lee and Shyun-Yeu Liu have contributed equally to this work.

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Lee, CH., Liu, SY., Chou, KC. et al. Tumor-Associated Macrophages Promote Oral Cancer Progression Through Activation of the Axl Signaling Pathway. Ann Surg Oncol 21, 1031–1037 (2014). https://doi.org/10.1245/s10434-013-3400-0

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  • DOI: https://doi.org/10.1245/s10434-013-3400-0

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