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

被引:168
作者
Akiyama, Kosuke [2 ]
Ohga, Noritaka
Hida, Yasuhiro [4 ]
Kawamoto, Taisuke
Sadamoto, Yoshihiro
Ishikawa, Shuhei
Maishi, Nako
Akino, Tomoshige [5 ]
Kondoh, Miyako
Matsuda, Aya [3 ]
Inoue, Nobuo [2 ]
Shindoh, Masanobu [3 ]
Hide, Kyoko [1 ]
机构
[1] Hokkaido Univ, Grad Sch Dent Med, Dept Vasc Biol, Kita Ku, Sapporo, Hokkaido 0608586, Japan
[2] Hokkaido Univ, Grad Sch Dent Med, Dept Gerodontol, Sapporo, Hokkaido 0608586, Japan
[3] Hokkaido Univ, Grad Sch Dent Med, Dept Oral Pathol & Biol, Sapporo, Hokkaido 0608586, Japan
[4] Hokkaido Univ, Grad Sch Med, Dept Surg Oncol, Sapporo, Hokkaido 0608586, Japan
[5] Hokkaido Univ, Grad Sch Med, Dept Renal & Genitourinary Surg, Sapporo, Hokkaido 0608586, Japan
关键词
BOX-BINDING PROTEIN-1; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; GROWTH-FACTOR; METRONOMIC CHEMOTHERAPY; PHASE-II; CANCER; ANGIOGENESIS; PACLITAXEL; EXPRESSION;
D O I
10.1016/j.ajpath.2011.11.029
中图分类号
R36 [病理学];
学科分类号
100103 [病原生物学];
摘要
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 resisting to paclitixel through MDRI 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 (Am J Pathol 2012, 180: 1283-1293; DOI: 10.1016/j.ajpath.2011.11.029)
引用
收藏
页码:1283 / 1293
页数:11
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