CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial-mesenchymal transition

Cancer stem cells (CSCs, also called cancer stem-like cells, CSLCs) can function as seed cells for tumor recurrence and metastasis. Here, we report that, in the presence of CD133(+) ovarian CSLCs, CD133-non-CSLCs can undergo an epithelialmesenchymal transition (EMT)-like process and display enhanced metastatic capacity in vitro and in vivo. Highly elevated expression of chemokine (C-C motif) ligand 5 (CCL5) and its receptors chemokine (C-C motif) receptor (CCR) 1/3/5 are observed in clinical and murine metastatic tumor tissues from epithelial ovarian carcinomas. Mechanistically, paracrine CCL5 from ovarian CSLCs activates the NF-kappa B signaling pathway in ovarian non-CSLCs via binding CCR1/3/5, thereby inducing EMT and tumor invasion. Taken together, our results redefine the metastatic potential of non-stem cancer cells and provide evidence that targeting the CCL5: CCR1/3/5-NF-kappa B pathway could be an effective strategy to prevent ovarian cancer metastasis.