TNF?-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2⁺ neutrophils.

ABSTRACT: Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis factor ? (TNF?)-activated MSCs significantly promoted tumor growth. However, the role of TNF?-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNF?-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNF?-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNF?-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and CXCL5) expressed by TNF?-activated MSCs efficiently recruited CXCR2⁺ neutrophils into tumor. These neutrophils were responsible for the pro-metastatic effect of MSCs since inhibition of this chemotaxis abolished increased neutrophil recruitment and tumor metastasis. The interaction between neutrophils and tumor cells resulted in markedly elevated metastasis-related genes by tumor cells, including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGF?. Importantly, in IL8^high human breast cancer samples, we also observed similar alterations of gene expression. Collectively, our findings demonstrate that TNF?-activated MSCs promote tumor metastasis via CXCR2⁺ neutrophil recruitment.

SUBMITTER: Yu PF 

PROVIDER: S-EPMC5290040 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature