Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity

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From: Pharmacogenomics(Vol. 16, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 13,437 words
Lexile Measure: 2140L

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Author(s): David Della-Morte [*] aff1 aff2 , Silvia Riondino aff1 aff2 , Patrizia Ferroni aff2 , Raffaele Palmirotta aff2 , Donatella Pastore aff1 , Davide Lauro aff1 , Fiorella Guadagni aff2 , Mario Roselli aff1

Keywords:

angiogenesis; cancer; elderly; genetics; single nucleotide polymorphisms; tumor prognosis; vascular endothelial growth factors; VEGF; VEGF inhibitors

Role of VEGF in cancer progression

Angiogenesis is a fundamental event both in physiological and pathological conditions, participating, respectively, in the process of tissue regeneration as well as in tumor growth and metastasis dissemination [ 1 ]. Vascular endothelial growth factors (VEGFs) are key regulators of angiogenesis - they are the most widely proangiogenic factors studied so far. The VEGF family consists of seven members (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and PlGF) sharing a common structure of eight characteristically spaced cysteine residues in a VEGF homology domain and acting through specific tyrosine kinase receptors (VEGFRs) to tightly regulate angiogenesis and lymphangiogenesis.

The crucial role of new vessel formation in cancer development is unquestioned. Pioneering studies by Folkman et al . have provided evidence that a cancer mass growing over 200 μm diameter requires neoangiogenesis to expand and invade surrounding tissues [ 2 ] and VEGF-A (from now on simply referred to as VEGF) is a major player in a complex balance involving proangiongenic stimuli and angiostatic factors [ 3 ]. VEGF is a dimeric glycoprotein whose role in neoangiogenesis is that of promoting both proliferation and migration of endothelial cells (ECs) [ 4,5 ], as well as activating EC survival and inhibiting apoptotic signaling [ 6 ], ultimately leading to formation of immature vasculature.

Among the other members of the family, little is known on the precise role of VEGF-B in tumor neoangiogenesis. Animal models suggested a role of VEGF-B in inflammatory angiogenesis and early tumor development, but the paucity of available data does not allow drawing any definitive conclusion [7 ]. On the other hand, VEGF-C and VEGF-D are primarily lymphangiogenic growth factors and VEGF-C has been shown to induce lymphangiogenesis in primary tumors and in draining sentinel lymph-nodes, thus promoting node metastasis [ 8 ]. Certain tumors such as breast, lung and gastrointestinal carcinomas have a propensity to metastasize through lymphatic vessels. For these patients, VEGF-C and VEGF-D might, thus, provide important prognostic information [ 9 ].

The VEGF family members bind to three receptors with tyrosine kinase activity, VEGFR-1 (fms-related tyrosine kinase-1 [Flt-1]), VEGFR-2 (kinase insert domain-containing receptor [KDR]) and VEGFR-3 (fms-related tyrosine kinase-4 [Flt-4]), although the angiogenic response to VEGF is mainly transduced through VEGFR-2 [10,11 ], which regulates the proliferation, migration and survival of endothelial cells both in physiologic and pathologic conditions [1,12,13 ]. In particular, intracellular downstream signaling pathways in response to VEGFR-2 activation comprise those of p85 PI3-Kinase (PI3K), PLC-[gamma], extracellular-regulated kinase (ERK), mediated by Ras-Raf-MEK-ERK [ 10,11 ] and the p38 mitogen-activated protein kinase (p38 MAPK), some of which are among the downstream effectors of VEGFR-1: PlC[gamma], p38 MAPK, p85 PI3K and growth factor receptor-bound-2 (Grb-2) [14,15 ].

Particularly interesting, given the close association reported between aging and cancer, are the recent findings demonstrating an impaired angiogenesis...

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Gale Document Number: GALE|A412067380