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many others. Thus, the identification of factors that regulate vascular homeostasis
and angiogenesis, and the elucidation of their mechanisms of action, is of great
experimental and clinical interest.
Among the various vasoregulatory factors so far identified, chromogranin A
(CgA), a protein secreted by many normal and neoplastic cells of the diffuse neuro-
endocrine system, is emerging as an important player. Indeed, a growing body of
evidence suggests that this protein and its fragments can regulate the endothelial
barrier function and can also work as a proteolytic-dependent angiogenic switch.
These studies and the potential role of CgA and its fragments as regulators of vas-
cular physiology in cancer and other pathophysiological conditions are reviewed
and discussed in the following.
2 CgA Structure and Expression
Human CgA is a glycosylated, sulphated and phosphorylated protein, 439-residue
long, stored in the secretory granules of many normal and neoplastic cells of the
diffuse neuroendocrine system (Portela-Gomes et al. 2010 ; Helle et al. 2007 ;
Taupenot et al. 2003 ; Deftos 1991 ; Janson et al. 1997 ). CgA is also expressed by
human polymorphonuclear neutrophils, by wound keratinocytes, and by myocar-
diocytes (Helle et al. 2007 ; Taupenot et al. 2003 ; Lugardon et al. 2000 ; Pieroni et al.
2007 ; Steiner et al. 1990 ; Biswas et al. 2010 ; Glattard et al. 2006 ; Radek et al. 2008 ;
Stridsberg et al. 2004 ). In addition, certain tumors, such as prostate cancer, non-
small cell lung cancer, breast cancer, gastric and colonic adenocarcinomas, may
undergo neuroendocrine differentiation and present focal expression of CgA
(Portel- Gomes et al. 2001 , 2010 ; Taupenot et al. 2003 ).
3 Physiological Functions of CgA
Within cells CgA has an important biological function in secretory granule biogen-
esis and control of secretion (Kim et al. 2001 ; Mosley et al. 2007 ; Courel et al. 2010 ;
Montesinos et al. 2008 ). These intracellular functions are described with more
details in other chapters of this book. CgA has also extracellular functions as precur-
sor of various bioactive peptides (Helle et al. 2007 ). Proteolytic processing of CgA
by intra-granular and/or extracellular proteases, such as prohormone convertase 1
and 2, furin, cathepsin L, plasmin, and thrombin, is important for the regulation of
its biological activity (Eskeland et al. 1996 ; Doblinger et al. 2003 ; Colombo et al.
2002a; Biswas et al. 2008 ; Biswas et al. 2009 ; Crippa et al. 2013 ; Bianco et al.
2016 ). CgA-derived fragments can exert a variety of biological effects: for example,
a fragment corresponding to residues 1–76, named vasostatin I (VS-I), inhibits
vasoconstriction in isolated blood vessels (Helle et al. 2007 ; Aardal and Helle 1992 ),
induces negative inotropism in isolated working frog and rat heart (Tota et al. 2008 ;
F. Curnis et al.