miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells

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.

Exosomal microRNAs synergistically trigger stromal fibroblasts in breast cancer

“…In particular, its upregulation has been associated with tumor growth, metastasis, and drug resistance in different types of cancer. 72 , 73 , 74 In breast cancer, exosomal miR-1246 has been used as diagnostic biomarker because of its high expression specificity.…”

The Roles of Tumor Endothelial Cells in Cancer Metastasis

“…Chemotherapy triggers TECs to suppress IGFBP7, and the upregulation of IGF1 activates the FGF4-FGFR1-ETS2 pathway in TECs and accelerates the conversion of tumor cells to chemoresistant tumor stem-like cells (58). Tumorderived microvesicles induce EC drug resistance via IL-6 upregulation, suggesting tumor secreting factor cause resistance of TEC to chemotherapy (59). Kikuchi et al reported that IL-8, induced by anti-cancer drugs, increases the expression of p-glycoprotein/ABCB1, which is a drug transporter in TECs of human bladder cancers (60) (Figure 3).…”

A New Antitumor Direction: Tumor-Specific Endothelial Cells

“…In addition to the different origins of TECs, TEC phenotypes are affected by TME. Comparing the TECs stimulated by two different metastatic tumor supernatants, found that the treatment of highly metastatic tumor conditioned medium increased the resistance of TECs to 5-fluorouracil (5-FU) (68). After coculture with lung cancer cells, human umbilical vein ECs showed enhanced cell motility and microvascular formation and a decrease in the percentage of apoptosis (69).…”