Tumor-associated macrophage-derived chemokine ligand 5 regulates the Hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway to promote breast cancer invasion and migration.

内容摘要

Tumor-associated macrophages (TAMs) are important components of the breast cancer (BC) microenvironment that contributes to tumor progression by secreting cytokines. Chemokine ligand 5 (CCL5) expression is upregulated in BC, but the specific mechanism of TAM-derived CCL5 in BC microenvironment remains elucidated. This article aims to explore the role of TAM-derived CCL5 in the progression of BC. M2-type TAMs were induced from Tohoku Hospital Pediatrics-1 (THP-1) monocytes. CCL5 expression in TAM cells was evaluated. The biological effects of recombinant or TAM-derived CCL5 on ZR-75-30 cells were examined using proliferation, migration, invasion assays, and epithelial-mesenchymal transition (EMT) markers. CCL5 was silenced in TAMs and hypoxia-inducible factor-1&#x3b1; (HIF-1&#x3b1;) was overexpressed to explore the downstream signaling pathway. CCL5 expression was significantly increased in TAMs compared with that in BC cells (P < 0.001). Recombinant CCL5 and TAM-conditioned medium promoted ZR-75-30 cell proliferation, migration, and invasion and EMT (P < 0.01), whereas CCL5 knockdown in TAMs markedly reversed these effects (P < 0.001). EMT-related changes, including decreased E-cadherin expression and increased Vimentin, matrix metalloproteinase (MMP)2, and MMP9 expression levels, were reversed by CCL5 silencing (P < 0.01). Inhibition of CCL5 significantly reduced HIF-1&#x3b1; and vascular endothelial growth factor (VEGF) expression levels (P < 0.001), and these reductions were rescued by HIF-1&#x3b1; overexpression (P < 0.01). Functional rescue experiments confirmed that HIF-1&#x3b1; overexpression restored cell proliferation and invasion and EMT suppressed by CCL5 knockdown. Angiogenesis was suppressed by CCL5 silencing and subsequently restored by HIF-1&#x3b1; overexpression (P < 0.001). TAM-derived CCL5 plays an oncogenic role in BC by regulating HIF-1&#x3b1;/VEGF pathway-mediated malignancy and angiogenesis.