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Original research
Cancer cell niche factors secreted from cancer-associated fibroblast by loss of H3K27me3
  1. Masahiro Maeda1,2,
  2. Hideyuki Takeshima1,
  3. Naoko Iida1,
  4. Naoko Hattori1,
  5. Satoshi Yamashita1,
  6. Hiroshi Moro1,
  7. Yoshimi Yasukawa1,
  8. Kazuhiro Nishiyama1,
  9. Taiki Hashimoto3,
  10. Shigeki Sekine3,
  11. Genichiro Ishii4,
  12. Atsushi Ochiai3,
  13. Takeo Fukagawa5,
  14. Hitoshi Katai5,
  15. Yoshiharu Sakai2,
  16. Toshikazu Ushijima1
  1. 1 Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
  2. 2 Department of Gastrointestinal Surgery, Faculty of Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  3. 3 Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
  4. 4 Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, Chiba, Japan
  5. 5 Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
  1. Correspondence to Dr Toshikazu Ushijima, Division of Epigenomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan; tushijim{at}


Objective Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells.

Design Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database.

Results CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal–epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration.

Conclusions H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.

  • cancer genetics
  • methylation
  • gastric cancer

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  • Contributors MM, HT, YS and TU designed the research; MM, HT, NH, HM, YY, KN and TH performed research; SS, GI, AO, TF and HK contributed to collection of samples and provided clinical information; MM and NI analysed data; MM, HT and TU wrote the paper.

  • Funding This study was supported by the Japan Agency for Medical Research and Development (AMED) under Grant Number JP17cm0106517h0002: Project for Cancer Research and Therapeutic Evolution (P-CREATE) and by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP16K19959.

  • Competing interests None declared.

  • Ethics approval The study was approved by the Institutional Review Boards at the National Cancer Center Hospital (2013–073) and East Hospital (2005–043) .

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication All surgically resected gastric specimens were obtained with written informed consent from all patients .

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