Mechanisms of resistance to vascular endothelial growth factor blockade
- 15 November 2011
- Vol. 118 (14), 3455-3467
- https://doi.org/10.1002/cncr.26540
Abstract
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.Keywords
This publication has 101 references indexed in Scilit:
- Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant MetastasisCancer Cell, 2009
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal Of Cancer, 2009
- Modes of resistance to anti-angiogenic therapyNature Reviews Cancer, 2008
- Integrins in angiogenesis and lymphangiogenesisNature Reviews Cancer, 2008
- Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trialThe Lancet, 2007
- Tumour vascularization: sprouting angiogenesis and beyondCancer and Metastasis Reviews, 2007
- AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma PatientsCancer Cell, 2007
- Regulation of angiogenesis by hypoxia: role of the HIF systemNature Medicine, 2003
- Clinical translation of angiogenesis inhibitorsNature Reviews Cancer, 2002
- Patterns and Emerging Mechanisms of the Angiogenic Switch during TumorigenesisCell, 1996