Abstract 1370: Tumor endothelial cells acquire drug resistance by MDR1 upregulation via VEGF signaling in tumor microenvironment

Tumor endothelial cells (TECs) are therapeutic targets in antiangiogenic therapy. Contrary to the traditional assumption, it has been reported that TECs can be genetically abnormal and might acquire drug resistance. In this study, mouse TECs and normal ECs (NECs) were isolated to investigate drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with upregulation of multidrug resistance 1 (MDR1) mRNA, which encodes the P-glycoprotein, compared to NECs. Normal human microvascular ECs (HMVECs) were cultured in tumor-conditioned medium (tumor CM) and were found to become more resistant to paclitaxel through MDR1 mRNA upregulation and nuclear translocation of Y-box-binding protein 1 (YB-1), which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in HMVECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGF receptor kinase inhibitor, Ki8751, and a PI3K/Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 upregulation. MDR1 upregulation via the VEGF/VEGFR pathway in the tumor microenvironment is one of the mechanisms of drug resistance acquired by TECs. We observed that VEGF secreted from tumors upregulated MDR1 through VEGFR2 and Akt activation. This is a novel mechanism of acquisition of drug resistance by TECs in a tumor microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1370. doi:1538-7445.AM2012-1370