hESC culture adaptation with reference to cancer (genomic and epigenetic)

Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)

1. Isolation and characterization of human embryonic stem cells and future applications in tissue engineering therapies

1.3. Stem cell quality and culture adaptation with reference to cancer

Cell culture can induce genomic and epigenetic changes in hESCs and should be controlled for. In fact, most cultured cells will have or acquire changes over time, and it is important to find out whether these changes are in an acceptable range for normal functionality. The hESC field is still relatively new and much remains to be understood before the right conclusions can be drawn from particular changes, making it necessary to screen for such changes in order to increase our knowledge. Genome instability and resistance of cell death through abnormalities are a hallmark of cancer (Hanahan and Weinberg, 2011), so introducing such abnormalities might be a big risk for future clinical applications. Some abnormalities enriched in hESC cultures are also found in tumours and might therefore carry a higher risk of inducing cancer-like changes.

Primordial germ cells and ESCs are closely related cell types as they originate from a similar developmental stage. Their similarity is partly mirrored in the abnormalities they acquire, with germ cell tumours (GCTs) most often amplifying chromosome 12p and gaining material from chromosome 17, much like culture-adapted hESCs (Summersgill et al., 2001); it has therefore been proposed that hESC culture adaptation may be used as a model for GCT malignancy (Harrison et al., 2007). During the malignant evolution of ECCs, differentiation capacity is lost in favour of proliferation proficiency, eventually leading to nullipotent ECCs with a high self-renewal capability. Culture-adapted cells may therefore lose some or all of their differentiation capacity and cause embryonal carcinoma-like tumours if undifferentiated cells are contaminating the differentiated cells used in clinical protocols. Impact of hESC culture-induced genomic and epigenetic changes in differentiated cells

Considering that hESCs can differentiate into any cell type found in the human body, there is a real risk that genomic or epigenetic abnormalities in these early stem cells cause more mature cell types to acquire cancer phenotypes. For example, trisomy 12, the most common abnormality in hESCs, is also associated with chronic lymphoid leukaemia (Juliusson et al., 1990), while gain of chromosome 17, particularly the long arm of 17, is strongly associated with neuroblastoma (Plantaz et al., 1997) and CNVs on chromosome locus 20q11 are associated with a variety of cancers (Beroukhim et al., 2010).

Epigenetically, there are many links between hESC abnormalities and neoplasia. The methylation of tumour-suppressor genes or the activation of oncogenes through epigenetic mechanisms might be a prime reason for the transformation of benign cells.


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