Background: Several lines of evidence suggest that the adult pituitary contains a population of tissue-specific stem cells capable of differentiating into hormone-producing cells. Previously, we have shown that Sox2+ve cells are able to self-renew and differentiate in vitro, suggesting that this population of undifferentiated cells may contain stem cells in vivo. When targeted with oncogenic mutations adult stem cells can become cancer stem cells, able to self-renew and give rise to cell progeny that colonise the tumour. Our research has revealed that pituitary embryonic precursors and adult stem cells may be involved in pituitary tumorigenesis. However, important questions remain unknown.
Objective and hypotheses: 1) Are Sox2+ve cells tissue-specific adult stem cells in the murine pituitary? 2) Can Sox2+ve cells generate cancer stem cells?
Method: We have performed genetic tracing of Sox2+ve cells in vivo using a Sox2CreERT2 mouse line to investigate the role of Sox2+ve cells in adult pituitary cell turn-over and in tumorigenesis.
Results: First, we demonstrate that Sox2+ve cells are able to self-renew and differentiate into all hormone-producing cells in vivo. In addition, we show that the expression of oncogenic beta-catenin specifically in Sox2+ve cells results in pituitary tumours resembling childhood craniopharyngioma. Finally, we reveal that tumours form in a non-cell autonomous manner whereby oncogenic Sox2+ve cells signal to surrounding cells leading to transformation and tumour growth. This novel paracrine model of tumorigenesis implies that the cell sustaining the oncogenic mutation and the cell of origin of the tumour are different.
Conclusion: 1) Sox2+ve cells are tissue-specific stem cells in the adult murine pituitary. 2) Sox2+ve cells can induce tumours in a paracrine manner, which is different to the cancer stem cell paradigm.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology