Tumor Endothelial Cells Acquire Drug Resistance by MDR1 Up-Regulation via VEGF Signaling in Tumor Microenvironment

Abstract

Tumor endothelial cells (TECs) are therapeutic targets in anti-angiogenic therapy. Contrary to the traditional assumption, TECs can be genetically abnormal and might also acquire drug resistance. In this study, mouse TECs and normal ECs were isolated to investigate the drug resistance of TECs and the mechanism by which it is acquired. TECs were more resistant to paclitaxel with the up-regulation of multidrug resistance (MDR) 1 mRNA, which encodes the P-glycoprotein, compared with normal ECs. Normal human microvascular ECs were cultured in tumor-conditioned medium (CM) and became more resistant to paclitaxel through MDR1 mRNA up-regulation and nuclear translocation of Y-box-binding protein 1, which is an MDR1 transcription factor. Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and Akt were activated in human microvascular ECs by tumor CM. We observed that tumor CM contained a significantly high level of VEGF. A VEGFR kinase inhibitor, Ki8751, and a phosphatidylinositol 3-kinase-Akt inhibitor, LY294002, blocked tumor CM-induced MDR1 up-regulation. MDR1 up-regulation, 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 up-regulated MDR1 through the activation of VEGFR2 and Akt. This process is a novel mechanism of the acquisition of drug resistance by TECs in the tumor microenvironment.

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

“…Notably, although several cancer cell models of mt-stabilizing drug resistance (e.g., taxol) have been concomitantly associated with reduced mt stability [47, 48], a precise characterization of tubulin dynamics in A549 cells with acquired MDR has not yet been well-described. We then identified whether the tubulin dynamics in the resistant phenotypes we developed had changed relative the mt status of parental A549 cells.…”

Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

“…The morphologies and functions of tumour vasculatures are known to differ from those of their normal counterparts67. Recent studies, including ours, revealed that tumour endothelial cells (TECs), components of tumour blood vessels, also differ from normal endothelial cells (NECs) in various aspects, including their angiogenic properties8, gene expression profiles9 and responses to growth factors1011 and chemotherapeutic drugs121314. Furthermore, TECs are cytogenetically abnormal1516.…”

Hypoxia Induces Multidrug Resistance via Enhancement of Epidermal Growth Factor-Like Domain 7 Expression in Non-Small Lung Cancer Cells

“…The tumor microenvironment, which leads to the development of MDR, includes an abnormal tumor vasculature, hypoxia, alteration in the expression of tumor suppressors/oncogenes (such as P53, ING4, and IL-24), and decreased PH [9,10,11]. Hypoxia is a common phenomenon in solid tumors and has the potential to promote a malignant progression by altering gene/protein expressions.…”