Signalling networks in focus
Vascular endothelial growth factor: Biology and therapeutic applications

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Abstract

While the development of anti-angiogenic therapy, as it pertains to cancer treatment, may still be in its infancy relative to well-established modalities such as chemotherapy, radiation, and surgery, major strides made in the past several decades have allowed translation of basic science discoveries in this field into clinical reality. The discovery of key molecular modulators of angiogenesis, notably vascular endothelial growth factor (VEGF), has catalyzed the development of numerous neutralizing therapeutic agents. The validity of VEGF inhibition as a therapeutic strategy has been well supported in randomized clinical trials, as well as U.S. Food and Drug Administration approval of the VEGF antagonists bevacizumab, sunitinib malate, sorafenib, pegaptinib and ranibizumab. Accordingly, this review will (1) briefly review the basic molecular biology of VEGF and (2) summarize recent progress in targeting the VEGF molecular pathway as therapy for angiogenic diseases such as cancer and age-related macular degeneration.

Introduction

The concept of tumor angiogenesis may have originated as early as a century ago with the observation of tumors as well-vascularized entities. However, the concept of angiogenesis inhibition as a therapeutic strategy against angiogenesis-dependent diseases, such as cancer and ocular disorders is comparatively new. Judah Folkman hypothesized in 1971 that tumor growth is dependent on angiogenesis, the process by which new blood vessels form from preexisting vasculature (Folkman, 1971). Based on observations that tumor growth does not occur continuously but rather as an abrupt and rapid growth occurring after extended periods (up to years) of non-neovascularized tumor dormancy, an ‘angiogenic switch’ was postulated wherein, neovascularization proceeds and is required for tumor growth beyond the pre-angiogenic dimensions of a few millimeters (Folkman & Kalluri, 2004).

This new concept in cancer biology implied the existence of biological modulators of angiogenesis and therapeutic uses thereof. In the three ensuing decades, intensive research has yielded a wealth of knowledge regarding both activators and inhibitors of angiogenesis. Chief among these was the purification in 1989 by Napoleone Ferrara of vascular endothelial growth factor (VEGF), also known as VEGF-A, as a potent endothelial mitogen from bovine pituitary follicular cell conditioned media (Ferrara & Henzel, 1989). Notably, the same polypeptide had been previously isolated as vascular permeability factor (VPF) by Harold Dvorak and colleagues (Senger et al., 1983). It is now known that VEGF plays a critical role in angiogenesis, vasculogenesis, and lymphangiogenesis, during embryonic and early post-natal development. Moreover, the role of VEGF as a key mediator of tumor angiogenesis is now well established, and forms the basis for using anti-VEGF drugs to treat neovascular diseases. In light of these important advances, this article will (1) review the role of VEGF in tumor angiogenesis, and (2) summarize current clinical progress in therapeutic targeting of VEGF.

Section snippets

Structure of VEGF

The VEGF gene family consists of numerous members including VEGF-A, -B, -C, -D and PlGF. The most well-characterized member, VEGF-A, exists as a homodimeric glycoprotein comprised of two identical 23 kDa subunits (Ferrara & Henzel, 1989). Of the numerous alternatively spliced isoforms of human VEGF-A, the 23 kDa monomer most closely corresponds to VEGF165 (i.e. 165 residues beyond the signal sequence), which is the most abundant and mitogenic VEGF isoform. Other main VEGF isoforms, including VEGF

Expression and regulation

The expression, availability, and activity of VEGF-A are modulated by several mechanisms including hypoxia, oncogene and tumor suppressor dysregulation, transcription factors, inflammatory mediators, and mechanical forces of shear stress and cell stretch (Fig. 1).

The VEGF-A gene is one of numerous genes regulated by hypoxia-inducible factor (HIF)-1α. Under hypoxic conditions, such as within large solid tumors, HIF-1α dimerizes with the constitutively expressed HIF-1β to form a transcription

Biological function

VEGF is involved in vasculogenesis, angiogenesis, and lymphangiogenesis during embryonic and postnatal development. Both single allele deletion of VEGF and gene knockouts of either VEGFR1 or VEGFR2 produce embryonic lethality from vasculogenic or angiogenic deficits (Ferrara et al., 1996; Fong, Rossant, Gertsenstein, & Breitman, 1995; Shalaby et al., 1995). VEGF has subsequently been implicated in a variety of functions during adult physiology including ovarian angiogenesis, endochondral bone

VEGF and disease

VEGF is a key effector of many post-natal pathological processes and diseases in the adult, and hence represents an important target of currently available and developing pharmacologic therapies. These conditions include neoplastic (solid tumors and hematological malignancies), ocular, inflammatory, vascular, and ischemic diseases (Ferrara et al., 2003).

The central role of VEGF in tumor angiogenesis and neoplastic diseases has been well established. Although VEGF is one of many pro-angiogenic

Clinical trials of VEGF inhibitors

The recent success of a growing number of VEGF antagonists in clinical trials underscores the critical role of VEGF in neovascular diseases and the efficacy of targeting VEGF as a therapeutic strategy. While the strategies for VEGF inhibition include diverse approaches such as soluble receptors, anti-receptor antibodies and aptamers (Gragoudas, Adamis, Cunningham, Feinsod, & Guyer, 2004; Holash et al., 2002, Miao et al., 2006), we focus below on clinical experience with monoclonal antibody and

Perspective

The concept of employing angiogenesis inhibition as a therapeutic strategy against neovascular diseases originated several decades ago. However, the breathtaking pace of both basic and clinical progress in this area has now transformed this elegant hypothesis into clinical reality confirmed by numerous randomized clinical trials. These successes have established anti-angiogenic therapy in general, and VEGF inhibition in specific, as a new treatment modality and in fact a new standard of care

Acknowledgements

We thank members of the Kuo laboratory for helpful comments and Kevin Wei for permission to cite unpublished observations. QTH. was supported by the Stanford Medical Scholars program. This review was supported by grants from the Brain Tumor Society, Prostate Cancer Foundation and NIH grants 1 R01 CA95654-01, 1 R01 NS052830-01 and 1 R01 HL074267-01 to CJK.

References (64)

  • H.Q. Miao et al.

    Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

    Biochemical and Biophysical Research Communications

    (2006)
  • J.A. Sivak-Callcott et al.

    Evidenced-based recommendations for the diagnosis and treatment of neovascular glaucoma

    Opthalmology

    (2001)
  • S. Soker et al.

    Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumour cells that bind VEGF165 via its exon 7-encoded domain

    The Journal of Biological Chemistry

    (1996)
  • S. Soker et al.

    Neuropilin-1 is expressed by endothelal and tumor cells as an isoform-specific receptor for vascular endothelial growth factor

    Cell

    (1998)
  • B.I. Terman et al.

    Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor

    Biochemical and Biophysical Research Communications

    (1992)
  • J. Waltenberger et al.

    Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor

    The Journal of Biological Chemistry

    (1994)
  • L.P. Aiello et al.

    Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders

    The New England Journal of Medicine

    (1994)
  • Brown, D. M., et al. (2006). Ranibizumab versus verteporfin for neovascular age-related macular degeneration. The New...
  • A.M. Byrne et al.

    Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF)

    Journal of Cellular and Molecular Medicine

    (2005)
  • F.L. Celletti et al.

    Vascular endothelial growth factor enhances atherosclerotic plaque progression

    Nature Medicine

    (2001)
  • U. Chakravarthy

    Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration

    Opthalmology

    (2006)
  • C. DeVries et al.

    The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor

    Science

    (1992)
  • J. Dong et al.

    VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis

    The European Molecular Biology Organization Journal

    (2004)
  • V. Easwaran et al.

    β-Catenin regulates vascular endothelial growth factor expression in colon cancer

    Cancer Research

    (2003)
  • R. Eferl et al.

    AP-1: A double edged sword in tumorigenesis

    Nature Review Cancer

    (2003)
  • S. Egginton et al.

    Unorthodox angiogenesis in skeletal muscle

    Cardiovascular Research

    (2003)
  • B. Escudier et al.

    Sorafenib in advanced clear-cell renal-cell carcinoma

    The New England Journal of Medicine

    (2007)
  • N. Ferrara et al.

    Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene

    Nature

    (1996)
  • N. Ferrara et al.

    The biology of VEGF and its receptors

    Nature Medicine

    (2003)
  • J. Folkman

    Tumor angiogenesis: Therapeutic implications

    The New England Journal of Medicine

    (1971)
  • J. Folkman

    Angiogenesis in cancer, vascular, rheumatoid and other disease

    Nature

    (1995)
  • J. Folkman et al.

    Cancer without disease

    Nature

    (2004)
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