Transforming Growth Factor Beta Promotes the Expansion of Cancer Stem Cells via S1PR3 by Ligand-Independent Notch Activation

Growing evidence suggests that cancer originates from cancer stem cells (CSCs), which can be identified by aldehyde dehydrogenase (ALDH) activity-based flow cytometr. However, the regulation of CSC growth is not fully understood. In the present study, we investigated the effects of Transforming Growth Factor-beta (TGF beta) in breast CSC expansion. Stimulation with TGF beta increased the ALDH-positive breast CSC population via the phosphorylation of sphingosine kinase 1 (SphK1), a sphingosine-1-phosphate (S1P)-producing enzyme, and subsequent SIP-mediated S1P receptor 3 (S1PR3) activation. These data suggest that TGF beta promotes breast CSC expansion via the ALIC5/SphK1/S1P/S1PR3 signaling pathway. Our findings provide new insights into the role of TGF beta in the regulation of CSCs.