Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4.
Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4.
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使用间充质干细胞（MSC）的细胞转移疗法具有显著的治疗潜力，但仍存在免疫排斥、栓塞形成和促进肿瘤进展的问题。由于MSC的作用模式高度依赖于其通过分泌生物活性分子的旁分泌效应，因此使用MSC的条件培养基（CM）的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。在此，我们解决了这个问题，并研究了可能的潜在分子机制。来源于人骨髓的MSC的CM极大地抑制了几种人肿瘤细胞系的体外生长和SCCVII鼠鳞状细胞癌细胞系的体内生长，具有减少的新血管形成。MSC-CM中的外来体仅部分参与抑制作用。CM含有多种细胞因子，包括胰岛素样生长因子结合蛋白（IGFBP）。其中，IGFBP-4极大地抑制了这些肿瘤的体外生长和血管生成，并且从CM中免疫耗竭IGFBP-4显著逆转了这些作用。值得注意的是，CM以部分IGFBP 4依赖的方式大大降低了AKT，ERK，IGF-1受体β和p38 MAPK的磷酸化，可能是通过其与IGF-1/2结合并阻断信号传导。去除IGFBP-4的CM也逆转了对体内肿瘤生长和新血管形成的抑制作用。因此，MSC-CM以IGFBP 4依赖性方式对肿瘤生长和新生血管形成具有有效的抑制作用，这表明使用MSC-CM的无细胞治疗甚至可能是癌症患者更安全的有前途的替代方案。我们发现，间充质干细胞（MSC）的条件培养基（CM）在体外和体内都能极大地抑制肿瘤生长和血管生成，而MSC-CM中的胰岛素样生长因子结合蛋白-4（IGFBP-4）在抑制作用中起着关键作用。这是第一份关于MSC-CM抗肿瘤作用的报告，其中IGFBP-4在CM中显示出重要作用。因此，使用MSC-CM的无细胞治疗可能是一种更安全和有前途的替代方案，甚至对癌症患者也是如此。
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. We found that conditioned medium (CM) of mesenchymal stem cells (MSCs) greatly inhibited in vitro and in vivo tumor growth and angiogenesis, and that insulin‐like growth factor binding protein‐4 (IGFBP‐4) in the MSC‐CM was critically involved in the inhibitory effects. This is the first report on the antitumor effects of MSC‐CM, of which IGFBP‐4 in the CM was shown to play important roles. Thus, cell‐free therapy using the MSC‐CM could be a safer and promising alternative for even cancer patients.
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影响因子：
5.2
作者：
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影响因子：
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4
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影响因子：
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