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

Abstract

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 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 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 PAI-1 and CCL5 signaling.

PAI‐1 induces Src inhibitor resistance via CCL5 in HER2‐positive breast cancer cells

“…To explore whether certain factors conferred to resistance of saracatinib, we evaluated the mRNA expression profile between parental cell line SKBR-3 and resistant cell line SKBR-3/SI. On the basis of our laboratory's previous study results, which hint that PAI-1 accelerates malignancy in breast cancer and is a prominent factor during tumor development and progression, 17 we further found that mRNA expression of PAI-1 was increased in the resistant cell line. Interestingly, gene ontology analysis of genes with over 2-fold change between SKBR-3/SI and SKBR-3 revealed an enrichment of factors involved in positive regulation of monocyte chemotaxis, which also was reported to interact with PAI-1 to enhance disease progression of breast cancer in our early data (Figure 2A).…”

“…On the basis of our laboratory's previous study results, which hint that PAI‐1 accelerates malignancy in breast cancer and is a prominent factor during tumor development and progression, we further found that mRNA expression of PAI‐1 was increased in the resistant cell line. Interestingly, gene ontology analysis of genes with over 2‐fold change between SKBR‐3/SI and SKBR‐3 revealed an enrichment of factors involved in positive regulation of monocyte chemotaxis, which also was reported to interact with PAI‐1 to enhance disease progression of breast cancer in our early data (Figure A) . Hence, we chose PAI‐1 for further research and confirmed that expression of PAI‐1 in SKBR‐3/SI was relatively higher in mRNA and protein levels than in SKBR‐3 (Figure B,C).…”

“…Interestingly, gene ontology analysis of genes with over 2-fold change between SKBR-3/SI and SKBR-3 revealed an enrichment of factors involved in positive regulation of monocyte chemotaxis, which also was reported to interact with PAI-1 to enhance disease progression of breast cancer in our early data (Figure 2A). 17 Hence, we chose PAI-1 for further research and confirmed that expression of PAI-1 in SKBR-3/SI was relatively higher in mRNA and protein levels than in SKBR-3 ( Figure 2B,C).…”

“…Our previous study found that PAI‐1 activated the CCL5/CCR5 axis in endothelial cells. In turn, CCL5 could induce PAI‐1 expression and secretion in breast cells, thus forming a positive feedback loop and facilitating the invasion behavior of cancer cells . Therefore, we speculated whether PAI‐1‐conferred Src inhibitor resistance was via CCL5.…”

“…Our recent study revealed that there might exist a positive feedback loop between PAI‐1 and CCL5 in breast cancer. PAI‐1 produced by breast cancer cells could induce CCL5 secretion from endothelial cells, which, in turn, stimulates the secretion of PAI‐1 from breast cancer cells, mutually leading to tumor progression . CCL5 is one of the members of the CC chemokine family of proteins, and notably CCL5 cooperating with its cognate receptor, CCR5, regulates various cell processes, including cell proliferation, motility and invasion in tumors.…”