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Article first published online: 15 NOV 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 14, pages 3455–3467, 15 July 2012
How to Cite
Abdullah, S. E. and Perez-Soler, R. (2012), Mechanisms of resistance to vascular endothelial growth factor blockade. Cancer, 118: 3455–3467. doi: 10.1002/cncr.26540
Editorial assistance was provided by Katie Gersh, PhD, of MedErgy, which was contracted by Boehringer Ingleheim Pharmaceuticals, Inc. for these services.
The authors met criteria for authorship as recommended by the International Committee of Medical Journal Editors, were fully responsible for all content and editorial decisions, and were involved at all stages of article development. The authors received no compensation related to the development of the manuscript.
- Issue published online: 2 JUL 2012
- Article first published online: 15 NOV 2011
- Manuscript Accepted: 9 AUG 2011
- Manuscript Revised: 28 JUL 2011
- Manuscript Received: 17 MAY 2011
- vascular endothelial growth factor;
Angiogenesis is essential for the growth of primary tumors and for their metastasis. This process is induced by factors, such as vascular endothelial growth factors (VEGFs), that bind to transmembrane VEGF receptors (VEGFRs). VEGF-A is the primary factor involved with angiogenesis; it binds to both VEGFR-1 and VEGFR-2. The inhibition of angiogenesis by obstructing VEGF-A signaling has been investigated as a method to treat solid tumors, but the development of resistance to this blockade has complicated treatment. The major mechanisms of this resistance to VEGF-A blockade include signaling by redundant receptors, such as the fibroblast growth factors, angiopoietin-1, ephrins, and other forms of VEGF. Other major mechanisms of resistance are increased metastasis of hypoxia-resistant tumor cells, recruitment of cell types capable of promoting VEGF-independent angiogenesis, and increased circulation of nontumor proangiogenic factors. Additional mechanisms of resistance to VEGF-A blockade include heterogeneity of responsiveness among tumor cells, use of anti-VEGF-A agents at insufficient doses or for insufficient duration, altered sensitivity to anti-VEGF-A agents by mutations in endothelial cells or vascular remodeling, maintenance of vascular sleeves that allow for easy regrowth of tumor vasculature upon discontinuation of therapy, vascular cooption, and intussusceptive angiogenesis. An understanding of these mechanisms may lead to the development of targeted therapies that overcome this resistance. Some of these approaches include the combined inhibition of redundant angiogenic pathways, proper patient selection for various therapies based on gene expression profiles, blockade of cellular migration by inhibition of colony-stimulating factor, or the use of agents to disrupt vascular architecture. Cancer 2012;3455–3467. © 2011 American Cancer Society.