Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells

// Steve Dingwall 1, 2 , Jung Bok Lee 1 , Borhane Guezguez 1 , Aline Fiebig 1 , Jamie McNicol 1 , Douglas Boreham 3 , Tony J. Collins 1, 4 , Mick Bhatia 1, 2, 4 1 McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada 2 Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, Canada 3 Department of Medical Physics, Faculty of Sciences, McMaster University, Hamilton, Canada 4 David Braley Human Stem Cell Screening Facility, McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada Correspondence to: Mick Bhatia, e-mail: mbhatia@mcmaster.ca Tony J. Collins, e-mail: tjc@mcmaster.ca Keywords: radiation resistance, cancer stem cells, human stem cells Received: March 23, 2015      Accepted: June 01, 2015      Published: June 13, 2015 ABSTRACT Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro . t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs.