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Differential role of epigenetic modulators in malignant and normal stem cells: a novel tool in preclinical in vitro toxicology and clinical therapy

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Abstract

Adult stem cells are primitive cells that undergo asymmetric division, thereby giving rise to one clonogenic, self-renewing cell and one cell able to undergo multipotent differentiation. Disturbance of this controlled process by epigenetic alterations, including imbalance of histone acetylation/histone deacetylation and DNA methylation/demethylation, may result in uncontrolled growth, formation of self-renewing malignant stem cells and eventually cancer. In view of this notion, several epigenetic modulators, in particular those with histone deacetylase inhibiting activity, are currently being tested in phase I and II clinical trials for their promising chemotherapeutic properties in cancer therapy. As chromatin modulation is also involved in regulation of differentiation, normal development, embryonic and adult stem cell functions and maintenance of their plasticity during embryonic organogenesis, the question can be raised whether predestined cell fate can be modified through epigenetic interference. And if so, could this strategy enforce adult stem cells to differentiate into different types of functional cells? In particular, functional hepatocytes seem important for preclinical toxicity screening of candidate drugs. This paper reviews the potential use and relevance of epigenetic modifiers, including inhibitors of histone deacetylases and DNA methyltransferases (1) to change cell fate and ‘trans’differentiate normal adult stem cells into hepatocyte-like cells and (2) to cure disorders, caused by uncontrolled growth of malignant stem cells.

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Abbreviations

AzaC:

decitabine, 5-Aza-2′-deoxycytidine

C/EBP:

CCAAT enhancer binding protein

CYP:

Cytochrome P450

DMSO:

Dimethylsulphoxide

DNMT:

DNA methyltransferases

ES:

Embryonic stem cells

HSC:

Haematopoietic stem cells

HNF:

Hepatocyte nuclear factor

HAT(s):

Histone acetyltransferase(s)

HDAC(s):

Histone deacetylase(s)

LETFs:

Liver-enriched transcription factors

MSC:

Mesenchymal stem cells

NCEs:

New chemical entities

TSA:

Trichostatin A

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Acknowledgements

This work was funded by a PhD grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen) and grants from the Research Council (OZR) of the Vrije Universiteit Brussel, Belgium. The project is also a part of the EU FP6 project, Liintop.

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Authors and Affiliations

  1. Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Sarah Snykers, Mathieu Vinken, Vera Rogiers & Tamara Vanhaecke

Authors
  1. Sarah Snykers
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  2. Mathieu Vinken
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  3. Vera Rogiers
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  4. Tamara Vanhaecke
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Corresponding author

Correspondence to Sarah Snykers.

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Sarah Snykers is a doctoral research fellow of the Vrije Universiteit Brussel (VUB), Belgium.

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Snykers, S., Vinken, M., Rogiers, V. et al. Differential role of epigenetic modulators in malignant and normal stem cells: a novel tool in preclinical in vitro toxicology and clinical therapy. Arch Toxicol 81, 533–544 (2007). https://doi.org/10.1007/s00204-007-0195-4

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  • DOI: https://doi.org/10.1007/s00204-007-0195-4

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