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

BMC Cancer

Masami Yamamoto¹  Tetsuya Tsukamoto²  Tetsuo Ohta³  Katsuya Gunjigake³  Daisuke Fujimori³  Jun Kinoshita³  Takahisa Yamaguchi³  Sachio Fushida³  Yusuke Nakamura³  Sachiyo Nomura⁴  Takashi Ohama⁵  Koichi Sato⁵ 

[1] Department of Applied Science, School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Musashino, Japan;Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan;Department of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, 920-8641, Kanazawa, Japan;Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;Laboratory of Veterinary Pharmacology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi, Japan;

关键词: Gastric cancer;    Peritoneal metastasis;    Immunocompetent mouse model;    Tumor microenvironment;   

DOI  :  10.1186/s12885-020-07477-x

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY