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Established fibrous peritoneal metastasis in an immunocompetent mouse model similar to clinical immune microenvironment of gastric cancer

Authors
  • Fujimori, Daisuke1
  • Kinoshita, Jun1
  • Yamaguchi, Takahisa1
  • Nakamura, Yusuke1
  • Gunjigake, Katsuya1
  • Ohama, Takashi2
  • Sato, Koichi2
  • Yamamoto, Masami3
  • Tsukamoto, Tetsuya4
  • Nomura, Sachiyo5
  • Ohta, Tetsuo1
  • Fushida, Sachio1
  • 1 Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan , Kanazawa (Japan)
  • 2 Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan , Yamaguchi (Japan)
  • 3 Nippon Veterinary and Life Science University, Musashino, Japan , Musashino (Japan)
  • 4 Fujita Health University School of Medicine, Toyoake, Japan , Toyoake (Japan)
  • 5 Graduate School of Medicine, The University of Tokyo, Tokyo, Japan , Tokyo (Japan)
Type
Published Article
Journal
BMC Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Oct 20, 2020
Volume
20
Issue
1
Identifiers
DOI: 10.1186/s12885-020-07477-x
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundPeritoneal metastasis (PM) in gastric cancer (GC) is characterized by diffusely infiltrating and proliferating cancer cells accompanied by extensive stromal fibrosis in the peritoneal space. The prognosis of GC with PM is still poor regardless of the various current treatments. In order to elucidate the cause of difficulties in PM treatment, we compared the tumor immune microenvironment (TME) in primary and PM lesions in GC. In addition, a PM model with fibrous stroma was constructed using immunocompetent mice to determine whether its TME was similar to that in patients.MethodsImmuno-histochemical analyses of infiltrating immune cells were performed in paired primary and PM lesions from 28 patients with GC. A C57BL/6 J mouse model with PM was established using the mouse GC cell line YTN16 either with or without co-inoculation of mouse myofibroblast cell line LmcMF with α-SMA expression. The resected PM from each mouse model was analyzed the immunocompetent cells using immunohistochemistry.ResultsThe number of CD8+ cells was significantly lower in PM lesions than in primary lesions (P < 0.01). Conversely, the number of CD163+ cells (M2 macrophages) was significantly higher in PM lesions than in primary lesions (P = 0.016). Azan staining revealed that YTN16 and LmcMF co-inoculated tumors were more fibrous than tumor with YTN16 alone (P < 0.05). Co-inoculated fibrous tumor also showed an invasive growth pattern and higher progression than tumor with YTN16 alone (P = 0.045). Additionally, YTN16 and LmcMF co-inoculated tumors showed lower infiltration of CD8+ cells and higher infiltration of M2 macrophages than tumors with YTN16 alone (P < 0.05, P < 0.05). These results indicate that LmcMF plays as cancer-associated fibroblasts (CAFs) by crosstalk with YTN16 and CAFs contribute tumor progression, invasion, fibrosis, and immune suppression.ConclusionsThis model is the first immunocompetent mouse model similar to TME of human clinical PM with fibrosis. By using this model, new treatment strategies for PM, such as anti-CAFs therapies, may be developed.

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