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VEGF-targeted therapy: mechanisms of anti-tumour activity

Key Points

  • Vascular endothelial growth factor (VEGF) mediates numerous changes within the tumour vasculature, including endothelial cell proliferation, migration, invasion, survival, chemotaxis of bone marrow-derived progenitor cells, vascular permeability and vasodilation.

  • There are several approaches to inhibiting VEGF signalling, including neutralization of the ligand or receptor by antibodies, and blocking VEGF receptor (VEGFR) activation and signalling with tyrosine kinase inhibitors.

  • VEGF-targeted therapy has been shown to be efficacious as a single agent in renal cell carcinoma and hepatocellular carcinoma, whereas it is only of benefit when combined with chemotherapy for patients with metastatic colorectal, non-small-cell lung and metastatic breast cancer.

  • VEGF-targeted therapy affects numerous cell types within the tumour microenvironment, including endothelial cells, haematopoietic progenitor cells, dendritic cells and tumour cells.

  • VEGF-targeted therapy has multiple mechanisms of action that might be dependent on tumour type.

  • VEGF-targeted therapy affects vascular function (flow and permeability) in addition to blocking further new blood vessel growth.

Abstract

Several vascular endothelial growth factor (VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. VEGF-targeted therapies were initially developed with the notion that they would inhibit new blood vessel growth and thus starve tumours of necessary oxygen and nutrients. It has become increasingly apparent, however, that the therapeutic benefit associated with VEGF-targeted therapy is complex, and probably involves multiple mechanisms. A better understanding of these mechanisms will lead to future advances in the use of these agents in the clinic.

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Figure 1: Vascular endothelial growth factor (VEGF) family members and receptors.
Figure 2: Blockade of incorporation of haematopoietic and endothelial progenitor cells.
Figure 3: Vascular endothelial growth factor (VEGF)-targeted therapy and vasoconstriction.
Figure 4: Vascular endothelial growth factor (VEGF)-targeted therapy induced normalization of the tumour vasculature.
Figure 5: A direct effect of vascular endothelial growth factor (VEGF)-targeted therapy on VEGF receptor 1 (VEGFR1) expression has been observed on human tumour cells implanted in mice.
Figure 6: Tumour-derived vascular endothelial growth factor (VEGF) inhibits maturation of dendritic cells (DCs).

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Authors and Affiliations

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Corresponding authors

Correspondence to Lee M. Ellis or Daniel J. Hicklin.

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Competing interests

Consulting (L.M.E.): ImClone Systems, Genentech

Research Support (L.M.E.): ImClone Systems, Amgen, Sanofi-Aventis

Employee of Schering-Plough Corporation (D.J.H.)

Ownership of stock in Schering-Plough Corporation (D.J.H.)

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DATABASES

National Cancer Institute

breast cancer

colorectal cancer

pancreatic cancer

National Cancer Institute Drug Dictionary

axitinib

bevacizumab

endostatin

interferon-α

oxaliplatin

paclitaxel

sorafenib

sunitinib

TNP-470

FURTHER INFORMATION

Angiogenesis inhibitors in clinical trials

Glossary

VEGF trap

A fully human soluble decoy receptor protein that consists of a fusion of the second immunoglobulin (Ig) domain of human VEGFR1 and the third Ig domain of human VEGFR2 with the constant region (Fc) of human IgG1. VEGF trap has a high affinity for all isoforms of VEGFA, as well as PlGF.

Progression-free survival

(PFS). The length of time that patients are free from any significant increase in tumour size or development of new tumours. PFS is measured as the time from start of treatment to the first measurement of cancer growth (by pre-defined criteria).

Vasculogenesis

This term is used for the de novo formation of new blood vessels from haematopoietic progenitor cells and normally takes place during embryogenesis. During tumour angiogenesis, EPCs migrate to sites of tumour growth and differentiate into tumour endothelial cells participating in new blood vessel growth.

Allogeneic

Allogeneic refers to cells or tissues from two different individual sources that are the same strain, but differ genetically in their major histocompatibility complex.

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Ellis, L., Hicklin, D. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8, 579–591 (2008). https://doi.org/10.1038/nrc2403

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