TY - JOUR
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
N1 - Funding Information:
We would like to thank Mari Fujiwara, Miyuki Yamamoto and Mikiko Shibuya for technical support and the Collaborative Research Resources, Keio University School of Medicine for technical support and reagents. Funding sources had no rule in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Funding Information:
This work was supported by JSPS Grant-in-Aid for Scientific Research : [grant number 15H04833 to A.E.H. and T.B.] and National Institute of Health [grant number R01 HL111190 to DMO].
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/5
Y1 - 2018/5
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
UR - http://www.scopus.com/inward/record.url?scp=85042788191&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2018.02.015
DO - 10.1016/j.lungcan.2018.02.015
M3 - Article
C2 - 29656749
AN - SCOPUS:85042788191
SN - 0169-5002
VL - 119
SP - 25
EP - 35
JO - Lung Cancer
JF - Lung Cancer
ER -