Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 15, 4158-4163 p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2016. Vol. 113, no 15, 4158-4163 p.
tumor; angiogenesis; VEGF; antiangiogenic therapy; adverse effects
IdentifiersURN: urn:nbn:se:liu:diva-127551DOI: 10.1073/pnas.1601649113ISI: 000373762400067PubMedID: 27035988OAI: oai:DiVA.org:liu-127551DiVA: diva2:926203
Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Swedish Diabetes Research Foundation; Swedish Childhood Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute Distinguished Professor award; Torsten Soderbergs Foundation; European Research Council Advanced Grant ANGIOFAT ; Knut Alice Wallenberg Foundation; Program of Introducing Talents of Discipline to Universities [B07035]; State Program of National Natural Science Foundation of China for Innovative Research Group ; NOVO Nordisk Foundation for the advanced grant2016-05-042016-05-032016-05-04