Identified in the 1980s, the vascular endothelial growth factor (VEGF) was first described as vascular permeability factor (VPF) and is now denoted as VEGF-A.1-5 The pivotal importance of this protein is reflected by its heterozygous embryonic lethality, which is induced by targeted inactivation of the VEGF gene,6'7 as well as the high homology of VEGF across species.8'9 Specifically, the "VEGF family'' of structurally related dimeric glycoproteins of the platelet-derived growth factor (PDGF) superfamily of growth factors includes VEGF-A, VEGF-B,10 VEGF-C,11 VEGF-D,12 VEGF-E, and placenta growth factor (PlGF).1314 Analysis of the crystal structure of VEGF-A shows an antiparallel homodimer, which is covalently linked by two disulfide bridges.15 In addition to homodimers, active forms of VEGF are also synthesized and secreted as heterodimers with other VEGF family members, such as PlGF, which only binds VEGF receptor-1 (VEGFR-1). Importantly, in contrast to pure PlGF homodimers, VEGF-PlGF heterodimers demonstrate potent mitogenic and chemotactic effects on endothelial cells, which are mediated via VEGFR-2.1617 VEGF-A is located at chromosome 6p21.3.18,19 The coding region spans ~14 kb and contains eight exons separated by seven introns. The VEGF promoter contains binding sites for Sp1, AP-1, and AP-2, through which protein kinase C (PKC) and protein kinase A (PKA) can mediate VEGF expression.20 Most importantly, the hypoxia response element (HRE) upstream of the VEGF gene binds hypoxia-induced factor-1 (HIF-1), thereby increasing VEGF expression.
To date, six VEGF isoforms generated by alternative mRNA splicing have been identified. The major isoforms of VEGF-A are2021: VEGFm, the predominant isoform, VEGFj65, VEGFj89, and VEGF206.4 These forms differ primarily in their bioavailability, which is conferred by heparin and heparan sulfate-binding domains encoded by exon 6 and exon 7. VEGF189 and VEGF206 contain additional stretches of basic residues, resulting in their nearly complete retention in the extracellular matrix (ECM) and to a lesser extent at the cell surface. VEGF206 binds most strongly to heparin. VEGFi65 lacks exon 6 and is secreted, but also remains bound by 50%-70% to the cell surface and the ECM via its heparin-binding sites. VEGF121, which lacks both exon 6 and exon 7, fails to bind heparin and is therefore a freely diffusible protein. The VEGF121, VEGF165, and VEGF189 forms are abundant and usually produced simultaneously. VEGF121 and VEGF165 isoforms induce mitogenic and permeability-enhancing activity on endothelial cells, whereas the other longer isoforms trigger only permeability-enhancing activity.21-23 In addition, uPA can cleave VEGFj89 within exon 6, thereby generating a truncated factor uPA-VEGF189 with mitogenic potential equivalent to VEGF165.24 Moreover, plasmin-induced cleavage of both VEGF165 and VEGF189 releases a bioactive carboxy-terminal domain (111-165) of VEGF.25
VEGF165, VEGF189, and VEGF206 levels are increased in several human malignancies including breast,26 lung,27 brain,28 pancreatic,29 ovarian,30 kidney, and bladder carcinomas.31 Less frequently expressed are the VEGF-A spliced forms VEGF145, VEGF183, VEGF162, and VEGF165b.32 VEGF145, for example, shows similar heparin affinity as VEGF165, and is expressed by both human multiple myeloma (MM) cells33 and Kaposi sarcoma-associated herpesvirus or human herpesvirus-8 (KSHV or HHV-8)-associated primary effusion lymphomas (PELs).34 Importantly, ECM-bound VEGF145 remains an active endothelial cell growth factor.35
VEGF is secreted by a variety of cells, including human hematologic tumor and MM cells.36 Hypoxia is a key regulator of VEGF expression via the HIF-1/von Hippel-Lindau tumor suppressor gene (VHL) pathway37'38; therefore, VEGF is the most highly expressed adjacent to necrotic areas.39,40 Besides hypoxia, growth factors and cytokines including PDGF, epidermal growth factor (EGF), fibroblast growth factor (FGF), tumor necrosis factor-a (TNF-a), tumor growth factor-a and (TGF-a, TGF-^1), keratinocyte growth factor, insulin-like growth factor-1 (IGF-1), interleukin-1p (IL-1^), and IL-641 upregulate transcription of VEGF mRNA.42 43 VEGF expression is also induced by UV-B and H2O244; mutant p53 (via PKC)45 and mutant Ras oncogenes46,47; proangiogenic oncogenes including Src, c-Myc, Fos, and Bcl-248; and acidosis.49 Recent studies in zebra fish demonstrate that bone morphogenetic protein (BMP)-activated Smad-binding elements including Smad1 and Smad5 as well as hedgehog signaling regulate VEGF expression and thereby contribute to hemangiogenic cell proliferation and adult stem cell formation.50 51 In addition, extracellular matrix metalloproteinase (EMMPRIN) contributes to tumor angiogenesis and growth by stimulating VEGF and matrix metalloproteinases (MMP) expression (Figure 4.1a).
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