The tumorigenicity of human embryonic and induced pluripotent stem cells

Key Points 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. 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. 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. 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. 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. 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. 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. 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. The unique ability of human pluripotent stem cells to self-renew and to dif