Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

Atsushi Mitsuhashi, Hisatsugu Goto, Atsuro Saijo, Trung Van The, Yoshinori Aono, Hirokazu Ogino, Takuya Kuramoto, Sho Tabata, Hisanori Uehara, Keisuke Izumi, Mitsuteru Yoshida, Hiroaki Kobayashi, Hidefusa Takahashi, Masashi Gotoh, Soji Kakiuchi, Masaki Hanibuchi, Seiji Yano, Hiroyasu Yokomise, Shoji Sakiyama and Yasuhiko Nishioka ()
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Atsushi Mitsuhashi: Institute of Biomedical Sciences, Tokushima University Graduate School
Hisatsugu Goto: Institute of Biomedical Sciences, Tokushima University Graduate School
Atsuro Saijo: Institute of Biomedical Sciences, Tokushima University Graduate School
Trung Van The: Institute of Biomedical Sciences, Tokushima University Graduate School
Yoshinori Aono: Institute of Biomedical Sciences, Tokushima University Graduate School
Hirokazu Ogino: Institute of Biomedical Sciences, Tokushima University Graduate School
Takuya Kuramoto: Institute of Biomedical Sciences, Tokushima University Graduate School
Sho Tabata: Institute of Biomedical Sciences, Tokushima University Graduate School
Hisanori Uehara: Institute of Biomedical Sciences, Tokushima University Graduate School
Keisuke Izumi: Institute of Biomedical Sciences, Tokushima University Graduate School
Mitsuteru Yoshida: Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School
Hiroaki Kobayashi: Fukui-ken Saiseikai Hospital
Hidefusa Takahashi: Municipal Tsuruga Hospital
Masashi Gotoh: Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University
Soji Kakiuchi: Institute of Biomedical Sciences, Tokushima University Graduate School
Masaki Hanibuchi: Institute of Biomedical Sciences, Tokushima University Graduate School
Seiji Yano: Cancer Research Institute, Kanazawa University
Hiroyasu Yokomise: Breast and Endocrinological Surgery, Faculty of Medicine, Kagawa University
Shoji Sakiyama: Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School
Yasuhiko Nishioka: Institute of Biomedical Sciences, Tokushima University Graduate School

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9792

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