LB36
Cell population dynamics of vitamin D induced reprogramming of malignant breast cancer cells
Wei Wu, Sui Huang, Stuart Kauffman
University of Calgary, Alberta, Canada
A growing body of evidence supports the notion that only a small subset of cancer cells within each tumour is capable of initiating tumour growth, often termed cancer stem cells. However, the dynamics with which such cells are generated and lost due to differentiation are unknown.
To begin to address this question, we treated the malignant and poorly differentiated breast cancer cell line MDA-MB-231, which express the cancer initiating cell markers (e.g, CD44+, ALDH+), with a well known chemopreventive agent, Vitamin D, and monitored the population dynamics. Vitamin D not only inhibited the growth of the malignant breast cancer cells, but also decreased the expression of the breast cancer stem cells marker CD44. Importantly, Vit. D treatment split the cell population into ALDH activity low (ALDH-L) and high (ALDH-H) subpopulations whose proportion was dose and time dependent. Consistently, Vit. D. prevented mammosphere formation. Upon withdrawal of vitamin D, the cells remembered the vitamin D effect by maintaining expression of the ALDH-L subpopulation for at least 120h, consistent with an irreversible state transition from the ALDH-H to the differentiated ALDH-L state. Furthermore, when the two subpopulations of cells were sorted with FACS and cultured separately, the ALDH-L subpopulation could not survive. In contrast, in a culture of a heterogeneous population of ALDH-L and ALDH-H, the presence of ALDH-H cells appeared to prevent the cell death of the ALDH-L cells.
This suggests that the ALDH-H cancer stem cells may secrete a survival factor acting on the differentiated-ALDH-L subpopulation. This relationship is currently being further characterised. We will also measure genome-wide gene expression or microRNA in these two fractions to learn more about the molecular basis of this spontaneous functional fractionation into two subpopulations. Understanding the molecular networks that govern the observed Vit.D induced transition is important for improving cancer differentiation therapy.
