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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1031-1037
Number of pages7
JournalAnnals of Surgical Oncology
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 2014

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Mouth Neoplasms
Macrophages
Coculture Techniques
Squamous Cell Carcinoma
Growth
Neoplasms
Genes
Epithelial-Mesenchymal Transition
Cultured Cells
Carcinogenesis
Immunohistochemistry
Neoplasm Metastasis

ASJC Scopus subject areas

  • Surgery
  • Oncology

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Tumor-associated macrophages promote oral cancer progression through activation of the Axl signaling pathway. / Lee, Chien Hsing; Liu, Shyun Yeu; Chou, Kuo Chou; Yeh, Chi-Tai; Shiah, Shine Gwo; Huang, Ren Yeong; Cheng, Jen Chan; Yen, Ching Yu; Shieh, Yi Shing.

In: Annals of Surgical Oncology, Vol. 21, No. 3, 03.2014, p. 1031-1037.

Research output: Contribution to journalArticle

Lee, Chien Hsing ; Liu, Shyun Yeu ; Chou, Kuo Chou ; Yeh, Chi-Tai ; Shiah, Shine Gwo ; Huang, Ren Yeong ; Cheng, Jen Chan ; Yen, Ching Yu ; Shieh, Yi Shing. / Tumor-associated macrophages promote oral cancer progression through activation of the Axl signaling pathway. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 3. pp. 1031-1037.
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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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AU - Lee, Chien Hsing

AU - Liu, Shyun Yeu

AU - Chou, Kuo Chou

AU - Yeh, Chi-Tai

AU - Shiah, Shine Gwo

AU - Huang, Ren Yeong

AU - Cheng, Jen Chan

AU - Yen, Ching Yu

AU - Shieh, Yi Shing

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N2 - 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.

AB - 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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