title: 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.
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan; Department of Gerodontology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Akiyama
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sadamoto
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Nako
authors.initials: N
authors.lastname: Maishi
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan; Department of Renal and Genitourinary Surgery, Graduate School of Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Akino
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Kondoh
authors.affiliation: Department of Oral Pathology and Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Department of Gerodontology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Department of Oral Pathology and Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.affiliation: Department of Vascular Biology, Graduate School of Dental Medicine, University of Hokkaido, Hokkaido, Japan. Electronic address: khida@den.hokudai.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; C499138:N-(2,4-difluorophenyl)-N'-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-fluorophenyl)urea; D010671:Phenylurea Compounds; D011804:Quinolines; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D017239:Paclitaxel