Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts

Ahmed E. Hegab, Mari Ozaki, Naofumi Kameyama, Jingtao Gao, Shizuko Kagawa, Hiroyuki Yasuda, Kenzo Soejima, Yongjun Yin, Robert D. Guzy, Yoshikazu Nakamura, David M. Ornitz, Tomoko Betsuyaku

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Abstract

Cancer-associated fibroblasts (CAFs) are known to promote tumourigenesis through various mechanisms. Fibroblast growth factor (FGF)/FGF receptor (FGFR)-dependent lung cancers have been described. We have developed a mouse model of lung adenocarcinoma that was constructed through the induction of Fgf9 overexpression in type 2 alveolar cells. The expression of Fgf9 in adult lungs resulted in the rapid development of multiple adenocarcinoma-like tumour nodules. Here, we have characterised the contribution of CAFs and the Fgf/Fgfr signalling pathway in maintaining the lung tumours initiated by Fgf9 overexpression. We found that CAF-secreted Fgf2 contributes to tumour cell growth. CAFs overexpressed Tgfb, Mmp7, Fgf9, and Fgf2; synthesised more collagen, and secreted inflammatory cell-recruiting cytokines. CAFs also enhanced the conversion of tumour-associated macrophages (TAMs) to the tumour-supportive M2 phenotype but did not influence angiogenesis. In vivo inhibition of Fgfrs during early lung tumour development resulted in significantly smaller and fewer tumour nodules, whereas inhibition in established lung tumours caused a significant reduction in tumour size and number. Fgfr inhibition also influenced tumour stromal cells, as it significantly abolished TAM recruitment and reduced tumour vascularity. However, the withdrawal of the inhibitor caused a significant recurrence/regrowth of Fgf/Fgfr-independent lung tumours. These recurrent tumours did not possess a higher proliferative or propagative potential. Our results provide evidence that fibroblasts associated with the Fgf9-induced lung adenocarcinoma provide multiple means of support to the tumour. Although the Fgfr blocker significantly suppressed the tumour and its stromal cells, it was not sufficient to completely eliminate the tumour, probably due to the emergence of alternative (resistance/maintenance) mechanism(s). This model represents an excellent tool to further study the complex interactions between CAFs, their related chemokines, and the progression of lung adenocarcinoma; it also provides further evidence to support the need for a combinatorial strategy to treat lung cancer.

Original languageEnglish
Pages (from-to)193-205
Number of pages13
JournalJournal of Pathology
Volume249
Issue number2
DOIs
Publication statusPublished - 2019 Oct 1

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Keywords

  • adenocarcinoma
  • cancer-associated fibroblasts
  • fibroblast growth factor 9
  • fibroblast growth factor receptor
  • lung

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Hegab, A. E., Ozaki, M., Kameyama, N., Gao, J., Kagawa, S., Yasuda, H., Soejima, K., Yin, Y., Guzy, R. D., Nakamura, Y., Ornitz, D. M., & Betsuyaku, T. (2019). Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer-associated fibroblasts. Journal of Pathology, 249(2), 193-205. https://doi.org/10.1002/path.5290