Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation
Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation
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DOI：
10.1016/j.bbrc.2018.01.034
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发表时间：
2018-02-05
影响因子：
3.1
通讯作者：
Maekawa, Taira
中科院分区：
文献类型：
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作者：
Nakagawa, Yoko;Ashihara, Eishi;Maekawa, Taira
新型分子靶向药物的出现改善了多发性骨髓瘤（MM）患者的预后。然而，MM仍然无法治愈，因为MM干细胞可能对这些药物具有耐药性。因此，重要的是进一步研究存在于缺氧骨髓小生境中的MM干细胞的生物学。在本研究中，我们建立并研究了低氧适应MM细胞（HA-MM）的特性，该细胞可以在低氧条件下（1%O-2）增殖超过六个月。在常氧条件下（20%O-2），HA-MM细胞的G 0分数大于亲本MM细胞。HA-MM细胞在初次和二次移植研究中具有增强的致瘤性。HA-MM细胞还表现出干细胞标志物的mRNA水平增加和自我更新能力增强，从而证明了MM干细胞的特征。这些细胞过表达磷酸化Smad 2，用转化生长因子（TGF）-β/Smad信号传导抑制剂处理在再铺板测定中降低了它们的克隆形成性。总之，MM细胞适应长期暴露的缺氧表现出干细胞的特性与TGF-β/Smad通路激活。(C)2018爱思唯尔公司All rights reserved.
The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O-2). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O-2). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-beta/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-beta/Smad pathway activation. (C) 2018 Elsevier Inc. All rights reserved.