Røsland Gro Vatne, Svendsen Agnete, Torsvik Anja, Sobala Ewa, McCormack Emmet, Immervoll Heike, Mysliwietz Josef, Tonn Joerg-Christian, Goldbrunner Roland, Lønning Per Eystein, Bjerkvig Rolf, Schichor Christian
Department of Biomedicine, University of Bergen, Bergen N-5009, Norway.
Cancer Res. 2009 Jul 1;69(13):5331-9. doi: 10.1158/0008-5472.CAN-08-4630. Epub 2009 Jun 9.
Human mesenchymal stem cells (hMSC) aid in tissue maintenance and repair by differentiating into specialized cell types. Due to this ability, hMSC are currently being evaluated for cell-based therapies of tissue injury and degenerative diseases. However, extensive expansion ex vivo is a prerequisite to obtain the cell numbers required for human cell-based therapy protocols. Recent studies indicate that hMSC may contribute to cancer development and progression either by acting as cancer-initiating cells or through interactions with stromal elements. If spontaneous transformation ex vivo occurs, this may jeopardize the use of hMSC as therapeutic tools. Whereas murine MSC readily undergo spontaneous transformation, there are conflicting reports about spontaneous transformation of hMSC. We have addressed this controversy in a two-center study by growing bone marrow-derived hMSC in long-term cultures (5-106 weeks). We report for the first time spontaneous malignant transformation to occur in 45.8% (11 of 24) of these cultures. In comparison with hMSC, the transformed mesenchymal cells (TMC) showed a significantly increased proliferation rate and altered morphology and phenotype. In contrast to hMSC, TMC grew well in soft agar assays and were unable to undergo complete differentiation. Importantly, TMC were highly tumorigenic, causing multiple fast-growing lung deposits when injected into immunodeficient mice. We conclude that spontaneous malignant transformation may represent a biohazard in long-term ex vivo expansion of hMSC. On the other hand, this spontaneous transformation process may represent a unique model for studying molecular pathways initiating malignant transformation of hMSC.
人间充质干细胞（hMSC）通过分化为特定细胞类型来协助组织维持和修复。由于这种能力，hMSC目前正在接受评估，用于组织损伤和退行性疾病的细胞疗法。然而，体外大量扩增是获得基于人类细胞的治疗方案所需细胞数量的先决条件。最近的研究表明，hMSC可能通过充当癌症起始细胞或通过与基质成分相互作用来促进癌症的发展和进展。如果体外发生自发转化，这可能会危及hMSC作为治疗工具的使用。虽然小鼠MSC很容易发生自发转化，但关于hMSC自发转化的报道却相互矛盾。我们通过在长期培养（5 - 106周）中培养骨髓来源的hMSC，在一项双中心研究中解决了这一争议。我们首次报告这些培养物中有45.8%（24个中的11个）发生了自发恶性转化。与hMSC相比，转化的间充质细胞（TMC）显示出显著提高的增殖率以及形态和表型的改变。与hMSC不同，TMC在软琼脂试验中生长良好，并且无法进行完全分化。重要的是，TMC具有高度致瘤性，当注射到免疫缺陷小鼠体内时会导致多个快速生长的肺部沉积物。我们得出结论，自发恶性转化可能是hMSC长期体外扩增中的一种生物危害。另一方面，这种自发转化过程可能代表了一种研究hMSC恶性转化起始分子途径的独特模型。
