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.