Potent antitumor effects of the conditioned medium of bone marrow‐derived mesenchymal stem cells via IGFBP‐4

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell‐free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC‐CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC‐CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin‐like growth factor binding proteins (IGFBPs). Among them, IGFBP‐4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP‐4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF‐1 receptor beta, and p38 MAPK in a partly IGFBP4‐dependent manner, possibly through its binding to IGF‐1/2 and blocking the signaling. The CM depleted of IGFBP‐4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC‐CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4‐dependent manner, suggesting that cell‐free therapy using MSC‐CM could be a safer promising alternative for even cancer patients.