Abstract
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.
Highlights
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes
We have reported that A375SM-derived tumor CM induced resistance to paclitaxel by upregulating MDR-1/ABCB1 in human normal endothelial cells (NECs):HMVEC18
We found that TECs isolated from A375SM tumors (A375SM-TECs) were resistant to 5-FU17, which is not a substrate of ABCB1, suggesting the presence of a different mechanism apart from ABCB1
Summary
Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. We found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs. Abbreviations TECs Tumor endothelial cells P-gp P-glycoprotein ABCB1 ATP-binding cassette sub-family B member 1 EVs Extracellular vesicles 5-FU 5-Fluorouracil IL-6 Interleukin-6 ECs Endothelial cells VEGF Vascular endothelial growth factor NECs Normal endothelial cells miRNA Micro RNA HMVECs Human dermis microvascular endothelial cells MEM Minimum essential medium FBS Fetal bovine serum. TECs clearly acquire drug resistance; the detailed mechanism of acquiring drug resistance in TECs has remained unknown
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