title: Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy.
abstract: Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden;
authors.forename: Guichun
authors.initials: G
authors.lastname: Huang
authors.affiliation: BioSciKin Biopharma, Nanjing, Jiangsu 210042, People's Republic of China;
authors.forename: Jingwu
authors.initials: J
authors.lastname: Zang
authors.affiliation: The First Affiliated Hospital of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang 310006, People's Republic of China;
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong 250012, People's Republic of China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester and National Institute of Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, United Kingdom;
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; Department of Cardiovascular Sciences, University of Leicester and National Institute of Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, United Kingdom; Department of Medicine, The Second Hospital of Wuxi, Wuxi, Jiangsu 214002, People's Republic of China; Department of Medicine and Health Sciences, Linköping University, 581 83 Linköping, Sweden yihai.cao@ki.se.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004702:Endocrine Glands / Q000098:blood supply* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A
keywords: VEGF; adverse effects; angiogenesis; antiangiogenic therapy; tumor