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首页> 外文期刊>Cell cycle >Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression
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Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

机译：细胞外酸性增强间充质干细胞，促进黑色素瘤进展

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Mesenchymal stem cells (MSC) participate to tumor stroma development and several evidence suggests that they play a role in facilitating cancer progression. Because melanoma often shows extracellular pH low enough to influence host cell as tumor cell behavior, the aim of this study is to elucidate whether acidity affects cross talk between MSC and melanoma cells to disclose new liaisons promoting melanoma progression, and to offer new therapeutic opportunities. We found that MSC grown in a low pH medium (LpH-MSC) stimulate melanoma xenografts more than MSC grown in a standard pH medium. LpH-MSC express a higher level of TGF that is instrumental of epithelial-to-mesenchymal transition (EMT)-like phenotype induction in melanoma cells. LpH-MSC profile also shows a switching to an oxidative phosphorylation metabolism that was accompanied by a forced glycolytic pathway of melanoma cells grown in LpH-MSC-conditioned medium. Metformin, an inhibitor of mitochondrial respiratory chain was able to reconvert oxidative metabolism and abrogate TGF expression in LpH-MSC. In addition, esomeprazole, a proton pump inhibitor activated in acidosis, blocked TGF expression in LpH-MSC through the downregulation of IkB. Both agents, metformin and esomeprazole, inhibited EMT profile in melanoma cells grown in LpH-MSC medium, and reduced glycolytic markers. Thus, acidosis of tumor microenvironment potentiates the pro-tumoral activity of MSC and orchestrates for a new potential symbiosis, which could be target to limit melanoma progression.
机译：间充质干细胞（MSC）参与肿瘤基质的发展，一些证据表明它们在促进癌症进展中起作用。由于黑素瘤通常显示出较低的细胞外pH值，足以影响宿主细胞作为肿瘤细胞的行为，因此本研究的目的是阐明酸性是否会影响MSC与黑素瘤细胞之间的串扰，以揭示促进黑素瘤进展的新联系并提供新的治疗机会。我们发现，与在标准pH培养基中生长的MSC相比，在低pH培养基（LpH-MSC）中生长的MSC对黑色素瘤异种移植的刺激更大。 LpH-MSC表达较高水平的TGF，这有助于黑色素瘤细胞上皮向间充质转化（EMT）样表型的诱导。 LpH-MSC谱还显示了向氧化磷酸化代谢的转换，伴随着在LpH-MSC条件培养基中生长的黑素瘤细胞的强制糖酵解途径。线粒体呼吸链抑制剂二甲双胍能够在LpH-MSC中恢复氧化代谢并消除TGF表达。此外，在酸中毒中激活的质子泵抑制剂埃索美拉唑通过下调IkB阻断LpH-MSC中TGF的表达。二甲双胍和埃索美拉唑均能抑制在LpH-MSC培养基中生长的黑色素瘤细胞的EMT谱，并降低糖酵解标记物。因此，肿瘤微环境的酸中毒增强了MSC的促肿瘤活性，并协调了新的潜在共生，这可能是限制黑素瘤进展的目标。

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