Hyperglycemia accelerated the metastasis of triple-negative breast cancer via promoting TNFα/Gli-1 axis in endothelial cells.

Diabetes mellitus (DM) is associated with a poor prognosis of aggressive breast cancer. Vascular dysfunction is commonly found during the development of both cancer and diabetes. We previously reported that the disruption of vascular endothelial phenotype induced by tumor necrosis factor-α (TNFα) accelerated the trans-endothelial metastasis of triple-negative breast cancer (TNBC). Herein, we explored the role of vascular endothelial cells in diabetes-induced TNBC metastasis. Both type 2 DM (T2DM) and type 1 DM (T1DM) enhanced the metastasis of TNBC in vivo. T2DM increased the expression of endothelial phenotype vascular endothelial cadherin (VE-cadherin), platelet-endothelial cell adhesion molecule (PECAM-1/CD31), and mesenchymal markers including vimentin and fibroblast specific protein-1 (FSP-1/S100A4) in tumor vessels. T1DM increased the expression of vimentin and FSP-1, but suppressed the expression of VE-cadherin in tumor vessels. Hyperglycemia elevated the production of TNFα in vivo and in vitro. TNFα reduced the trans-endothelial electrical resistance (TEER) value of both human mammary microvascular endothelial cells (HMMECs) and human umbilical vein endothelial cells (HUVECs). Expressions of vimentin and α-smooth muscle actin (α-SMA) were also increased in TNFα-treated both HMMECs and HUVECs. The number of trans-endothelial migrated MDA-MB-231 cells through TNFα-treated HMMECs or HUVECs monolayer was elevated. Moreover, glioma-associated oncogene 1 (Gli-1) was remarkably accumulated in the nucleus of TNFα-stimulated HMMECs and DM-induced tumor vessels. Both Gli-1 siRNA and GANT61 (an inhibitor of Gli-1) could abrogate the increased TNBC trans-endothelial migration through TNFα-treated ECs. We demonstrated that DM might promote TNBC metastasis via activating the TNFα/Gli-1 axis initiated vascular endothelial mesenchymal-like phenotype.