Details

Autor(en) / Beteiligte

• Kishi, Shingo
• Fujiwara‐Tani, Rina
• Honoki, Kanya
• Sasaki, Rika
• Mori, Shiori
• Ohmori, Hitoshi
• Sasaki, Takamitsu
• Miyagawa, Yoshihiro
• Kawahara, Isao
• Kido, Akira
• Tanaka, Yasuhito
• Kuniyasu, Hiroki

Titel

Oxidized high mobility group B‐1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells

Ist Teil von

• Cancer science, 2022-08, Vol.113 (8), p.2904-2915

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Wiley Online Library

Beschreibungen/Notizen

• High mobility group box‐1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post‐translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three‐fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM‐MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM‐MSCs pretreated with oxidized HMGB1 were co‐cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co‐culture with reduced HMGB1‐pretreated BM‐MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1–MSC axis may be an important target for cancer therapy. Reduced HMGB1 promoted chemotaxis of MSCs, decreased their stemness, and promoted their differentiation. In contrast, oxidized HMGB1 increased stemness and promoted proliferation of MSCs, and chemotaxis was decreased. Oxidized HMGB1 recruits MSCs into tumors and reprograms them, thereby increasing cancer stemness and promoting liver metastasis.