以间充质干细胞（MSCs）为基础的细胞转移疗法具有显著的治疗潜力，但还存在免疫排斥、栓塞形成和促进肿瘤进展的问题。由于MSCs主要通过分泌生物活性分子的旁分泌作用发挥作用，因此使用MSCs的条件培养基（CM）进行无细胞疗法是一种有吸引力的选择。然而，MSC-CM对肿瘤进展的影响尚未完全阐明。因此，我们探讨了这个问题，并研究了可能的潜在分子机制。人骨髓来源的MSCs的CM极大地抑制了多种人类肿瘤细胞系的体外生长和SCCVII小鼠鳞状细胞癌细胞系的体内生长，同时减少了血管生成。 MSC-CM中的外泌体仅在抑制作用中部分参与。CM包含多种细胞因子，包括胰岛素样生长因子结合蛋白（IGFBPs）。其中，IGFBP-4极大地抑制了这些肿瘤和血管生成的体外生长，通过从CM中免疫清除IGFBP-4可显着逆转这些作用。值得注意的是，CM在某种程度上依赖于IGFBP4，大大降低了AKT，ERK，IGF-1受体β和p38 MAPK的磷酸化，可能通过其对IGF-1/2的结合并阻止信号传导。除去IGFBP-4的CM也逆转了对体内肿瘤生长和血管生成的抑制作用。因此，MSC-CM在以IGFBP4为依赖的方式中对肿瘤生长和血管生成具有强大的抑制作用，表明使用MSC-CM的无细胞疗法可能是一个更安全的有前途的选择，即使是癌症患者也适用。 本文受版权保护。保留所有权利。

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.This article is protected by copyright. All rights reserved.