title: Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab.
abstract: Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy.
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mitsuhashi
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Hisatsugu
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Atsuro
authors.initials: A
authors.lastname: Saijo
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Van The
authors.initials: VT
authors.lastname: Trung
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ogino
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuramoto
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Thoracic Surgery, Fukui-ken Saiseikai Hospital, Funabashi 7-1, Wadanaka-cho, Fukui, Fukui 918-8503, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Internal Medicine, Municipal Tsuruga Hospital, 1-6-60 Mishima-cho, Tsuruga, Fukui 914-8502, Japan.
authors.forename: Hidefusa
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of General Thoracic, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Gotoh
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.affiliation: Department of General Thoracic, Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Yokomise
authors.affiliation: Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Sakiyama
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, Tokushima 770-8503, Japan.|JST, CREST, Tokyo 102-0076, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000068258:Bevacizumab / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D000068258:Bevacizumab