Mechanisms of resistance to vascular endothelial growth factor blockade

Shaad E. Abdullah, Roman Perez-Soler

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3455-3467
Number of pages13
JournalCancer
Volume118
Issue number14
DOIs
StatePublished - Jul 15 2012

Fingerprint

Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Vascular Endothelial Growth Factor Receptor
Blood Vessels
Neoplasms
Ephrins
Angiopoietin-1
Neoplasm Metastasis
Fibroblast Growth Factor 1
Colony-Stimulating Factors
Transcriptome
Patient Selection
Therapeutics
Endothelial Cells
Maintenance
Mutation
Growth

Keywords

  • cancer
  • resistance
  • signaling
  • vascular endothelial growth factor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mechanisms of resistance to vascular endothelial growth factor blockade. / Abdullah, Shaad E.; Perez-Soler, Roman.

In: Cancer, Vol. 118, No. 14, 15.07.2012, p. 3455-3467.

Research output: Contribution to journalArticle

Abdullah, Shaad E. ; Perez-Soler, Roman. / Mechanisms of resistance to vascular endothelial growth factor blockade. In: Cancer. 2012 ; Vol. 118, No. 14. pp. 3455-3467.
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