Regulation of Toll-Like Receptors in Cancer Stemness: A Pro-Inflammatory Switch Model
M Gallagher, S Elbaruni, R Flavin, C Martin, A Laios, S O'Toole, O Sheils, JJ O'Leary. Trinity College Dublin, Dublin, Ireland
Background: Ovarian cancer, one of the most common cancers affecting women, is often detected in an advanced stage, resulting in a high mortality rate. Ovarian cancer has been shown to be associated with cancer stem cells (CSCs), the extensive self-renewal and differentiation of which is believed to drive primary tumourigenesis while contributing to metastasis and recurrence. As malignancies often arise at the site of chronic or prolonged inflammation, we have assessed whether inflammatory events may play a role in cancer stemness.
Design: Microarray data from early differentiation of teratocarcinoma derived CSCs revealed differential expression of a collection of inflammatory genes. Pro-inflammatory genes identified were validated over a two-week differentiation time course in Ntera2 (pluripotent) and 2102Ep (Nullipotent) teratocarcinoma CSCs using quantitative realtime PCR.
Results: Gene expression data indicates the presence of a two-pronged pro-inflammatory component of the switch of CSCs from self-renewal to differentiated growth, which involves alterations in expression of multiple genes. 1. MyD88-dependent TLR4 signaling is constitutively active in self-renewing CSCs and is downregulated upon differentiation resulting in decreases in pro-inflammatory cytokines NF-B and TNF. 2. Upon differentiation an alternative pro-inflammatory response may result in release of IFN- via Jak-STAT signaling. This mechanism likely results in a pro-malignancy microenvironment that facilitates tumourigenesis.
Conclusions: Teratocarcinoma CSCs employ pro-inflammatory signals during the switch from self-renewal to differentiated growth. This may provide a pro-malignancy microenvironment. Future work will focus on assessing the necessity of the mechanism towards the disruption of these genes to potentially remove stemness from CSCs.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 169, Tuesday Afternoon