Prognostic and predictive role of vascular endothelial growth factor polymorphisms in breast cancer

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Date: Jan. 2015
From: Pharmacogenomics(Vol. 16, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 10,587 words
Lexile Measure: 2150L

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Author(s): Angelos Koutras [*] aff1 , Vasiliki Kotoula aff2 aff3 , George Fountzilas aff3 aff4

Keywords:

angiogenesis; bevacizumab; breast cancer; polymorphisms; predictive; prognostic; SNP; vascular endothelial growth factor; VEGF

Angiogenesis

Angiogenesis represents an essential process in the pathogenesis of cancer, since tumors depend on the development of their own vessel network that will supply cancer cells with oxygen and nutrients. The initiation of angiogenesis necessitates the so-called angiogenic switch, which is triggered by the predominance of stimulatory over inhibitory angiogenic factors [1 ]. The vascular endothelial growth factor (VEGF) pathway constitutes the most dominant angiogenic pathway. The VEGF family comprises five homologous members: VEGF-A (usually referred to as VEGF), VEGF-B, VEGF-C, VEGF-D and PlGF. These factors represent ligands for VEGF tyrosine-kinase receptors (VEGFR-1, VEGFR-2 and VEGFR-3). These receptors, which are expressed primarily in endothelial cells, are activated by VEGFs. More specifically, binding of VEGFs to the extracellular domain of VEGFRs results in receptor dimerisation. Consequently, the cytoplasmatic catalytic function of the receptor is activated, leading to autophosphorylation on tyrosine residues. This autophosphorylation of the receptor activates a cascade of signalling pathways including phosphatidylinositol 3-kinase (PI3-K)-Akt and Ras-Raf-MEK mitogen-activated protein kinase (MAPK)-dependent pathway. VEGFR-1 is activated by VEGF, VEGF-B and PlGF, while VEGFR-2 is activated mainly by VEGF. The expression of VEGF by cancer cells is controlled by several factors. Among them, hypoxia constitutes a major mediator of VEGF production through hypoxia-inducible transcription factors. The most important mediator of angiogenesis in tumors is VEGF. Through alternative RNA splicing, various isoforms of VEGF are generated. The activation of VEGFR-2 by VEGF promotes vessel permeability. Additionally, signal transduction pathways stimulated by VEGFR-2 induce the migration, proliferation and survival of endothelial cells [2-5 ]. It has been shown that breast cancer cells often overexpress VEGF [ 6,7 ].

Targeting the VEGF pathway in breast cancer

VEGF is the principal regulator of neovascularization. Moreover, VEGF is necessary to sustain newly formed vessels and plays significant roles in the function and maintenance of mature vascular beds. The VEGF pathway is a potentially attractive target in the treatment of patients with cancer [ 8 ]. In addition, anti-VEGF drugs may be useful in other diseases (such as diabetic retinopathy or amyotrophic lateral sclerosis), where genetic insights into their pathophysiology has demonstrated the role of VEGF [ 9,10 ]. Bevacizumab is a humanized recombinant IgG1 mAb that selectively binds to all major isoforms of human VEGF with high affinity. This interaction precludes the binding of VEGF to its receptors and eliminates activation of the VEGF pathway. Even though the precise mechanisms of action are not entirely elucidated yet, the current data suggest that anti-VEGF therapies are characterized by a wide spectrum of antitumor properties. It has been demonstrated that the inhibition of VEGF by bevacizumab leads to regression of existing abnormal vessel network of the tumor, through apoptosis of endothelial cells [11 ]. Furthermore, it has been shown that the inhibition of VEGF induces the normalization of the structural and functional abnormalities in the residual tumor vasculature [12 ], which may increase the penetration...

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Gale Document Number: GALE|A412067381