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

Abstract

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.

IGF2BP2-meidated m 6 A modification of CSF2 reprograms MSC to promote gastric cancer progression

“…Increasingly researches stress the reciprocal crosstalk of cancer cells and MSCs in the progression of tumor, which can partly account for the complexity and heterogeneity of tumor-stroma connections. Oxidized HMGB1 recruited MSCs into tumors, and promoted proliferation of MSCs, thereby increasing colorectal cancer stemness and promoting liver metastasis [23]. MSCs in hypoxia microenvironment could promote liver cancer progression by activating YAP and through COX2/PGE 2 /EP4 axis [24].…”

IGF2BP2-meidated m6A modification of CSF2 reprograms MSC to promote gastric cancer progression

“…Increasing studies highlight the reciprocal crosstalk between cancer cells and MSCs in tumor progression, adding new complexity and heterogeneity to tumor-stroma interactions. For instance, oxidized HMGB1 has been shown to recruit MSCs into tumors, thereby increasing colorectal cancer stemness and facilitating liver metastasis [ 23 ]. MSCs in hypoxic microenvironments promote liver cancer progression by activating YAP and the COX2/PGE 2 /EP4 axis [ 24 ].…”

Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma

“…MIA-P or MIA-GEM cells (1 × 10 7 ) in 100 mL HBSS (Wako) were mixed with 100 mL of Matrigel solution (#356234, Corning Inc., Corning, NY, USA) and inoculated into mouse scapular tissue subcutaneously. [51]. Cells were pretreated with 3 µm of antisense or control S-ODN (Table 5) for 3 d. Thereafter, the mice were treated with GEM (30 mg/kg body weight) intraperitoneally, twice weekly.…”

“…Consecutive 4-µm sections were immunohistochemically stained using the immunoperoxidase technique [51]. We used 0.2 µg/mL of anti-MAST4, anti-AKT3 (Table 5), and secondary antibodies (Medical and Biological Laboratories, Nagoya, Japan).…”