文章：

人胚胎和诱导多能干细胞的致瘤性

The tumorigenicity of human embryonic and induced pluripotent stem cells

原文发布日期：2011-03-10

DOI: 10.1038/nrc3034

类型: Review Article

开放获取: 否

要点：

1. Human embryonic stem cells (HESCs) share cellular and molecular phenotypes with tumour cells and cancer cell lines. When injected into immunodeficient mice, HESCs form teratomas. The tumorigenicity of HESCs is a major hurdle, which must be confronted before the achievements from this field of research can be safely translated into the clinic.
2. Sharing with HESCs their basic properties of self-renewal and pluripotency, human induced pluripotent stem cells (HiPSCs) also share their tumorigenic traits. However, HESCs and HiPSCs are not identical, and a rapidly accumulating body of work suggests considerable differences between these two pluripotent cell types.
3. The transcription factors commonly used for reprogramming somatic cells into HiPSCs (OCT4, SOX2, MYC and krupple-like factor 4 (KLF4)) are highly expressed in various types of cancer. HiPSCs are commonly derived using integrating vectors, thus creating a risk for genetic alterations and for reactivation of the reprogramming factors at later stages.
4. HiPSCs can acquire chromosomal aberrations, even more readily than HESCs. These can result from their somatic cells of origin, reprogramming stress and during culture adaptation. Aneuploidy of pluripotent stem cells has been suggested to increase their tumorigenicity.
5. Epigenetic differences between HESCs and HiPSCs also affect their tumorigenicity. The reprogramming process is often accompanied by epigenetic alterations. The epigenetic 'memory' of the cells might also contribute to their tumorigenicity.
6. Self-renewal is important for the tumorigenic traits of HESCs and HiPSCs, and cell cycle-related genes are crucial for an efficient reprogramming process. These genes are also involved in the genomic instability that characterizes pluripotent cells.
7. Owing to genetic and epigenetic causes, HiPSCs are more tumorigenic than HESCs, and harbour a risk for the development of teratocarcinomas and possibly somatic tumours.
8. In order to develop safe HESC- and HiPSC-based treatments, the tumorigenicity hurdle must be overcome. Three general strategies to cope with this risk have been suggested: terminal differentiation or complete elimination of residual pluripotent stem cells from culture; interfering with tumour-progression genes to prevent tumour formation from the residual pluripotent cells; and tumour detection and elimination after its initial formation in the patient's body.

要点翻译：

1. 人胚胎干细胞（HESCs）与肿瘤细胞及癌细胞系具有相似的细胞和分子表型。当注入免疫缺陷小鼠体内时，HESCs会形成畸胎瘤。其致瘤特性是这一研究领域成果安全转化至临床应用前必须克服的主要障碍。
2. 与HESCs同样具备自我更新和多能性基本特性的人诱导多能干细胞（HiPSCs），也继承了致瘤特性。然而HESCs与HiPSCs并非完全相同，快速积累的研究证据表明这两种多能细胞类型存在显著差异。
3. 常用于将体细胞重编程为HiPSCs的转录因子（OCT4、SOX2、MYC和krupple样因子4（KLF4））在多种癌症类型中高表达。HiPSCs通常通过整合载体获得，这可能导致遗传改变及重编程因子在后续阶段被重新激活的风险。
4. HiPSCs比HESCs更容易获得染色体畸变。这些畸变可能源于其原始体细胞、重编程应激以及培养适应过程。多能干细胞非整倍体性已被证实会增强其致瘤性。
5. HESCs与HiPSCs之间的表观遗传差异也会影响其致瘤性。重编程过程常伴随表观遗传改变，细胞的表观遗传“记忆”也可能促进其致瘤特性。
6. 自我更新能力对HESCs和HiPSCs的致瘤特性至关重要，而细胞周期相关基因对高效重编程过程具有关键作用。这些基因也参与多能细胞特有的基因组不稳定性过程。
7. 由于遗传和表观遗传因素，HiPSCs比HESCs具有更强致瘤性，且存在形成畸胎癌及体细胞肿瘤的风险。
8. 为开发基于HESC和HiPSC的安全疗法，必须克服致瘤性障碍。目前提出三种通用应对策略：对培养物中残留多能干细胞进行终末分化或完全清除；干扰肿瘤进展基因以阻止残留多能细胞形成肿瘤；在患者体内肿瘤初始形成后进行检测与清除。

英文摘要：

The unique abilities of human pluripotent stem cells to self-renew and to differentiate into cells of the three germ layers make them an invaluable tool for the future of regenerative medicine. However, the same properties also make them tumorigenic, and therefore hinder their clinical application. Hence, the tumorigenicity of human embryonic stem cells (HESCs) has been extensively studied. Until recently, it was assumed that human induced pluripotent stem cells (HiPSCs) would behave like their embryonic counterparts in respect to their tumorigenicity. However, a rapidly accumulating body of evidence suggests that there are important genetic and epigenetic differences between these two cell types, which seem to influence their tumorigenicity.

摘要翻译： 

人类多能干细胞自我更新并分化为三胚层细胞的独特能力，使其成为再生医学未来的宝贵工具。然而，这些特性也使其具有致瘤性，从而阻碍了它们的临床应用。因此，人胚胎干细胞（HESCs）的致瘤性已被广泛研究。直到最近，人们还认为人诱导多能干细胞（HiPSCs）在致瘤性方面与其胚胎对应物表现相似。然而，迅速积累的大量证据表明，这两种细胞类型之间存在重要的遗传和表观遗传差异，这些差异似乎会影响它们的致瘤性。

原文链接：

The tumorigenicity of human embryonic and induced pluripotent stem cells