Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

Endothelial cells (ECs) in the tumor microenvironment have been reported to play a more active role in solid tumor growth and metastatic dissemination than simply providing the physical structure to form conduits for blood flow; however, the involvement of ECs in the process of triple-negative breast cancer (TNBC) metastasis has not been addressed. Here, we demonstrate that ECs-when mixed with TNBC cells-could increase TNBC cell metastatic potency. After treatment with TGF-β to induce endothelial-mesenchymal transition (EMT), TNBC cells could produce plasminogen activator inhibitor-1 (PAI-1) and stimulate the expression and secretion of the chemokine, CCL5, from ECs, which then acts in a paracrine fashion on TNBC cells to enhance their migration, invasion, and metastasis. CCL5, in turn, accelerates TNBC cell secretion of PAI-1 and promotes TNBC cell metastasis, thus forming a positive feedback loop. Moreover, this enhanced metastatic ability is reversible and dependent on CCL5 signaling via the chemokine receptor, CCR5. Of importance, key features of this pathway are manifested in patients with TNBC and in The Cancer Genome Atlas database. Taken together, our results suggest that ECs enhance EMT-induced TNBC cell metastasis via PAI-1 and CCL5 signaling and illustrate the potential of developing new PAI-1- and CCL5-targeting therapy for patients with TNBC.-Zhang, W., Xu, J., Fang, H., Tang, L., Chen, W., Sun, Q., Zhang, Q., Yang, F., Sun, Z., Cao, L., Wang, Y., Guan, X. Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling.

Zhang W ，Xu J ，Fang H ，Tang L ，Chen W ，Sun Q ，Zhang Q ，Yang F ，Sun Z ，Cao L ，Wang Y ，Guan X ... -  《-》

Epithelial-mesenchymal transition induced PAI-1 is associated with prognosis of triple-negative breast cancer patients.

Epithelial-mesenchymal transition (EMT) is a key developmental program in which epithelial cells lose polarity and become mesenchymal cells, and that is often activated during cancer invasion and metastasis. Triple negative breast cancer (TNBC) patients have a relatively aggressive biological behavior with a high risk of distant recurrence and metastasis. Here, we stimulated TNBC cells to undergo EMT, and detected the protein expression profiles of the protein secretion. High-throughput data showed that EMT could promote TNBC cells to secret PAI-1. We found that TNBC-secreted PAI-1 could increase cell growth, migration and invasion, and the expression of EMT markers in the TNBC cell lines and xenograft PAI-1-/- mice model. Using a tissues microarray of 165 TNBC patients and published breast cancer database, we found PAI-1 expression was significantly elevated in the breast cancer tissues, comparing with the normal adjacent tissues and was associated with prognosis of patients with TNBC. Taken together, our results suggests an important role of PAI-1 in the EMT process of TNBC cells and illustrates the great potential of developing PAI-1-targeting therapy for clinical TNBC patients.

Xu J ，Zhang W ，Tang L ，Chen W ，Guan X ... -  《-》

Cancer cell CCL5 mediates bone marrow independent angiogenesis in breast cancer.

Sax MJ ，Gasch C ，Athota VR ，Freeman R ，Rasighaemi P ，Westcott DE ，Day CJ ，Nikolic I ，Elsworth B ，Wei M ，Rogers K ，Swarbrick A ，Mittal V ，Pouliot N ，Mellick AS ... -  《-》

Simultaneous blockade of IL-6 and CCL5 signaling for synergistic inhibition of triple-negative breast cancer growth and metastasis.

Jin K ，Pandey NB ，Popel AS 《-》

Emodin inhibits epithelial‑mesenchymal transition and metastasis of triple negative breast cancer via antagonism of CC‑chemokine ligand 5 secreted from adipocytes.

Song X ，Zhou X ，Qin Y ，Yang J ，Wang Y ，Sun Z ，Yu K ，Zhang S ，Liu S ... -  《-》