Bone marrow mesenchymal stem cells promote prostate cancer cell stemness via cell–cell contact to activate the Jagged1/Notch1 pathway

摘要

Mesenchymal stem cells (MSCs) play a crucial role in cancer development and tumor resistance to therapy in prostate cancer, but the influence of MSCs on the stemness potential of PCa cells by cell–cell contact remains unclear. In this study, we investigated the effect of direct contact of PCa cells with MSCs on the stemness of PCa and its mechanisms. First, the flow cytometry, colony formation, and sphere formation were performed to determine the stemness of PCaMSCs, and the expression of stemness-related molecules (Sox2, Oct4, and Nanog) was investigated by western blot analysis. Then, we used western blot and qPCR to determine the activity levels of two candidate pathways and their downstream stemness-associated pathway. Finally, we verified the role of the significantly changed pathway by assessing the key factors in this pathway via in vitro and in vivo experiments. We established that MSCs promoted the stemness of PCa cells by cell–cell contact. We here established that the enhanced stemness of PCaMSCs was independent of the CCL5/CCR5 pathway. We also found that PCaMSCs up-regulated the expression of Notch signaling-related genes, and inhibition of Jagged1-Notch1 signaling in PCaMSCs cells significantly inhibited MSCs-induced stemness and tumorigenesis in vitro and in vivo. Our results reveal a novel interaction between MSCs and PCa cells in promoting tumorigenesis through activation of the Jagged1/Notch1 pathway, providing a new therapeutic target for the treatment of PCa.