Development of arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic Acid/protein kinase D signaling 

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within arteriolar niche in human estrogen receptor positive (ER + ) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 signaling pathway in combination with inhibition of CD36 function may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and eliminating CSCs.