Familial Nasopharyngeal Carcinoma 6

Molecular Signaling Pathways in Nasopharyngeal Cancer 33diffusion and solid tumor growth is limited to 2–3 mmin diameter (Folkman 1990, 1995a, 1995b, 2002).Angiogenesis is controlled by pro- and antiangiogenicfactors for endothelial cells. However, thetight suppression of angiogenesis that is present inphysiologic state is absent in tumor tissues (Ferrara2002). Any one step from the expression of ligandsand receptors, ligand–receptor engagement, or efferentsignal transduction cascade can be upregulatedin tumors. As such, not only the process of angiogenesisis active, the characteristics of tumoral endothelialcells and perivascular structures are substantiallydifferent from their normal counterparts.3.3.2Vascular Endothelial Growth Factorsand ReceptorsVascular endothelial growth factor (VEGF) is a specificgrowth factor group for endothelial cells, and is consideredto be the most cardinal vascular growth factorprompting tumor angiogenesis. The VEGF family consistsof seven ligands derived from distinct genes:VEGF A–E, as well as placenta growth factor (PGF) 1and PGF 2 (Ferrara et al. 2003). Among all familymembers of VEGF, VEGF-A is the most potent andspecific growth factor for endothelial cells (Ferrara2004). VEGF-A has been shown to stimulate endothelialcell mitogenesis and migration. It is also a vasodilatorand increases microvascular permeability;it was originally referred to as vascular permeabilityfactor and eventually renamed VEGF (Ferrara2009; Verheul and Pinedo 2007). Figure 3.3 illustratedthe biological functions of VEGF (Fig. 3.3).VEGF is associated with most steps in angiogenesis.In addition to the functions described above, itcan also induce proteinases leading to remodeling ofthe extracellular matrix and suppress dendritic cellmaturation. (Pepper et al. 1991; Gerber et al. 1998;Mandriota et al. 1995). The production of VEGF andsubsequent angiogenesis can be triggered by a numberof cellular and microenvironmental factors, includinghypoxia, balance between oncogenes and tumor suppressorgenes, expression of certain cellular receptors,and circulating levels of other growth factors andcytokines (Hicklin and Ellis 2005). Among theknown promoting factors, hypoxia is of particularimportance in tumor growth. Hypoxia remains animportant trigger of VEGF expression even after formationof neovascularization in tumor tissues (Levyet al. 1997; Maxwell et al. 1999; Ferrara et al. 2003).Activation ofcoagulation cascadeTissue factorvWF releaseAngiogenesisEC proliferationMigrationTube formationHyperpermeabilityVascular homeostasisEC survivalVascular integrityKidney functionProtein filtrationPodocyte survivalVascular EndothelialGrowth FactorImmunomodulationDendritic cell functionThyroid functionStimulation ofthryroid cellsBlood pressureVasodilation(NO and PGI 2 release)Baroreceptor responseBone marrow functionHaematopoiesis and/ormyelopoiesisFig. 3.3. The various biological functions of VEGF EC endothelial cell; NO nitric oxide; PGI2 prostacyclin; VEGF vascularendothelial growth factor; vWF von Willebrand factor