miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis

Abstract

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126*, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126* directly inhibit stromal cell-derived factor-1 alpha (Sdf-1α) expression, and indirectly suppress the expression of chemokine (C–C motif) ligand 2 (Ccl2) by cancer cells in an Sdf-1α-dependent manner. miR-126/miR-126* expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126* downregulation and poor metastasis-free survival of breast cancer patients.

Epidermal Growth Factor–like Domain 7 Predicts Response to First-Line Chemotherapy and Bevacizumab in Patients with Metastatic Colorectal Cancer

“…When comparing EGFL7 and miR126 VA (adjacent sections), we detected a positive, significant relationship in biopsies and tumor resections, respectively, indicating some degree of common transcriptional regulation of miR126 and EGFL7. This is not surprising, because transcription of the EGFL7 gene also involves transcription of miR126 (22)(23)(24).…”

Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes

“…CCL2 is produced by tumor and stromal cells, such as mesenchymal stem cells and fibroblasts (15,40,41). CCL2 levels in the lungs and peripheral blood increased significantly after tumor inoculation (Fig.…”

“…Their recruitment from the bone marrow (BM) to peripheral tissues is mediated mainly by chemokine-chemokine receptor complexes such as the CCL2/CCR2 system (12,13). Even in metastatic cascades, the CCL2-CCR2 axis is a key pathway for IM recruitment, which in turn promotes tumor colonization and metastasis by secreting VEGFA (14,15). Moreover, the prevalence of IMs in the peripheral blood, as induced by the CCL2-CCR2 axis, correlates with liver metastasis, adverse outcome, and shorter patient survival in pancreatic cancer (16).…”

The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets

“…4T1 cells transduced with miR-126 did not exhibit a difference in proliferation and migration in comparison to non-transfected 4T1 cells, but rather showed suppressed formation of lung metastases after surgical removal of the primary tumor from fat pads (138). Stromal-derived factor 1 (SDF-1), the ligand of CXCR4, was identifed as a direct target of miR-126.…”

“…Another property of miR-126 expressed in BC cells is the recruitment of MSCs and inflammatory monocytes, both promoting BC metastasis (138). 4T1 cells transduced with miR-126 did not exhibit a difference in proliferation and migration in comparison to non-transfected 4T1 cells, but rather showed suppressed formation of lung metastases after surgical removal of the primary tumor from fat pads (138).…”