Journal
ONCOGENE
Volume 30, Issue 46, Pages 4632-4644Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2011.175
Keywords
transformation; human stem cells; self-renewal; differentiation
Funding
- Canadian Institute of Health Research (CIHR)
- Canadian Cancer Society (CCS)
- Ontario Institute of Cancer Research (OICR)
- Canadian Cancer Society Research Institute (CCSRI)
- Canada Research Chair Program
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The in vivo relationship between human tumor cells and interacting normal cells in their local environment is poorly understood. Here, using a uniquely developed in vitro co-culture system for human embryonic stem cells (hESCs), we examined the interactions between transformed and normal human stem cells. Co-culture of transformed-hESCs (t-hESCs) with normal hESCs led to enhanced self-renewal and niche independence in normal hESCs. Global gene expression analysis of normal hESCs after timed exposure to t-hESCs indicated a transition of the molecular network controlling the hESC state, which included epigenetic changes, towards neoplastic features. These included enhanced pluripotent marker expression and a differentiation blockade as major hallmark changes. Functional studies revealed a loss in normal terminal differentiation programs for both hematopoiesis and neural lineages after normal stem cell co-culture with transformed variants. This transmission of neoplastic properties from t-hESCs to normal hESCs was dependent on direct cell-cell contact. Our study indicates that normal human stem cells can co-opt neoplastic cancer stem cell properties, raising the possibility that assimilation of healthy cells towards neoplastic behavior maybe a contributing feature of sustained tumorigenesis in vivo. Oncogene (2011) 30, 4632-4644; doi:10.1038/onc.2011.175; published online 30 May 2011
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