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Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy

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journal contribution
posted on 29.08.2019, 15:58 by Y Zhang, Y Yang, K Hosaka, G Huang, J Zang, F Chen, NJ Samani, Y Cao
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.

Funding

Swedish Research Council, the Swedish Cancer Foundation, the Swedish Diabetes Research Foundation, the Swedish Childhood Cancer Foundation, the Karolinska Institute Foundation, the Karolinska Institute Distinguished Professor award, the Torsten Soderbergs Foundation, European Research Council Advanced Grant ANGIOFAT (Project 250021), the Knut Alice Wallenberg Foundation, the NOVO Nordisk Foundation for the advanced grant, Program of Introducing Talents of Discipline to Universities (Grant B07035), and the State Program of National Natural Science Foundation of China for Innovative Research Group (Grant 81321061).

History

Citation

Proceedings of the National Academy of Sciences of the United States of America, 2016, 113 (15), pp. 4158-4163

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences

Version

VoR (Version of Record)

Published in

Proceedings of the National Academy of Sciences of the United States of America

Publisher

National Academy of Sciences of the USA

issn

0027-8424

eissn

1091-6490

Acceptance date

03/03/2016

Copyright date

2016

Available date

29/08/2019

Language

en

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