Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms

Ahmed E. Hegab, Mari Ozaki, Shizuko Kagawa, Junko Hamamoto, Hiroyuki Yasuda, Katsuhiko Naoki, Kenzo Soejima, Yongjun Yin, Tomonari Kinoshita, Tomonori Yaguchi, Yutaka Kawakami, David M. Ornitz, Tomoko Betsuyaku

Research output: Contribution to journalArticle

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Abstract

Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. Materials and methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.

Original languageEnglish
Pages (from-to)25-35
Number of pages11
JournalLung Cancer
Volume119
DOIs
Publication statusPublished - 2018 May 1

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Fibroblast Growth Factor 9
Macrophages
Growth
Neoplasms
Adenocarcinoma of lung
Carcinogenesis
Fibroblasts

Keywords

  • Adenocarcinoma
  • FGF9
  • Lung
  • Mouse model of cancer
  • Tumor associated macrophages

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms. / Hegab, Ahmed E.; Ozaki, Mari; Kagawa, Shizuko; Hamamoto, Junko; Yasuda, Hiroyuki; Naoki, Katsuhiko; Soejima, Kenzo; Yin, Yongjun; Kinoshita, Tomonari; Yaguchi, Tomonori; Kawakami, Yutaka; Ornitz, David M.; Betsuyaku, Tomoko.

In: Lung Cancer, Vol. 119, 01.05.2018, p. 25-35.

Research output: Contribution to journalArticle

Hegab, AE, Ozaki, M, Kagawa, S, Hamamoto, J, Yasuda, H, Naoki, K, Soejima, K, Yin, Y, Kinoshita, T, Yaguchi, T, Kawakami, Y, Ornitz, DM & Betsuyaku, T 2018, 'Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms', Lung Cancer, vol. 119, pp. 25-35. https://doi.org/10.1016/j.lungcan.2018.02.015
Hegab, Ahmed E. ; Ozaki, Mari ; Kagawa, Shizuko ; Hamamoto, Junko ; Yasuda, Hiroyuki ; Naoki, Katsuhiko ; Soejima, Kenzo ; Yin, Yongjun ; Kinoshita, Tomonari ; Yaguchi, Tomonori ; Kawakami, Yutaka ; Ornitz, David M. ; Betsuyaku, Tomoko. / Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms. In: Lung Cancer. 2018 ; Vol. 119. pp. 25-35.
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abstract = "Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. Materials and methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.",
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T1 - Tumor associated macrophages support the growth of FGF9-induced lung adenocarcinoma by multiple mechanisms

AU - Hegab, Ahmed E.

AU - Ozaki, Mari

AU - Kagawa, Shizuko

AU - Hamamoto, Junko

AU - Yasuda, Hiroyuki

AU - Naoki, Katsuhiko

AU - Soejima, Kenzo

AU - Yin, Yongjun

AU - Kinoshita, Tomonari

AU - Yaguchi, Tomonori

AU - Kawakami, Yutaka

AU - Ornitz, David M.

AU - Betsuyaku, Tomoko

PY - 2018/5/1

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N2 - Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. Materials and methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.

AB - Objectives: Tumor-associated macrophages (TAMs) are known to promote tumorigenesis but the mechanism(s) remain elusive. We have developed a mouse model of lung cancer that is initiated through an inducible overexpression of fibroblast growth factor 9 (FGF9) in type-2 pneumocytes. Expression of FGF9 in adult lungs resulted in a rapid development of multiple adenocarcinoma-like tumor nodules, and is associated with an intense immunological reaction. The purpose of this study is to characterize the immune response to the FGF9-induced lung adenocarcinoma and to determine the contribution of TAMs to growth and survival of these tumors. Materials and methods: We used flow cytometry, immunostaining, RT-PCR and in vitro culture system on various cell populations isolated from the FGF9-induced adenocarcinoma mouse lungs. Results: Immunostaining demonstrated that the majority of the inflammatory cells recruited to FGF9-induced lung tumors were macrophages. These TAMs were enriched for the alternatively activated (M2) macrophage subtype. TAMs performed a significantly high immune suppressive function on T-cells and displayed high levels of arginase-1 expression and activity. The growth and colony forming potential of tumor cells was induced by co-culture with TAMs. Additionally, TAMs were shown to promote fibroblast proliferation and angiogenesis. TAMs had high expression of Tgf-β Vegf, Fgf2, Fgf10, Fgfr2 and several matrix metalloproteinases; factors that play multiple roles in supporting tumor growth, immune protection, fibroblast activation and angiogenesis. Conclusion: Our results provide evidence that the Fgf9-induced lung adenocarcinoma is associated with recruitment and activation of M2-biased TAMs, which provided multiple means of support to the tumor. This model represents an excellent means to further study the complex interactions between TAMs, their related chemokines, and progression of lung adenocarcinoma, and adds further evidence to support the importance of TAMs in tumorigenesis.

KW - Adenocarcinoma

KW - FGF9

KW - Lung

KW - Mouse model of cancer

KW - Tumor associated macrophages

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