90
essential hypertension or in normotensive subjects with a family history of hyper-
tension and increased epinephrine secretion (O’Connor et al. 2002 ). On the other
hand, plasma catestatin levels, measured with a commercial assay kit, were found
increased in patients with coronary heart disease and after acute myocardial infarc-
tion (Meng et al. 2013 ; Liu et al. 2013 ). However, also in this case, the catestatin-
containing molecular entities detected by these assays in plasma were not
characterized.
Regarding cancer, different proportions of full-length CgA and fragments have
been detected in healthy subjects and multiple myeloma patients, including CgA1-
439, CgA1-373, CgA1-76 and other fragments (Bianco et al. 2016 ). The relative
levels of circulating pro- and anti-angiogenic molecules (e.g. CgA1-373/CgA1-439
and CgA1-373/CgA1-76) were higher in these patients at diagnosis, compared to
healthy subjects, suggesting that a proteolytic mechanism capable of “turning-on”
the CgA-angiogenic switch was active in multiple myeloma. Furthermore, the bone
marrow plasma of patients contained higher levels of CgA1-373 and lower levels of
CgA1-439 than peripheral-blood plasma, suggesting that cleavage at R373 occurred
in the bone marrow (Bianco et al. 2016 ). Relevant to the proposed role of CgA in
angiogenesis and vascular homeostasis, the ratio between pro- and anti-angiogenic
forms correlates with the bone marrow plasma levels of VEGF and FGF-2, two pro-
angiogenic factors known to have key roles in the cross-talk between myeloma
cells, stromal cells and endothelial cells in the bone marrow (Bianco et al. 2016 ;
Ribatti et al. 2006 ; Jakob et al. 2006 ). Mechanistic studies showed that multiple
myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage
by activating the plasminogen activator/plasmin system (Bianco et al. 2016 ). These
findings suggest that CgA and its fragments may represent new players in the regu-
lation of angiogenesis in the bone marrow microenvironment of multiple myeloma
patients and, possibly, also in other diseases.
8 CgA and Tumor Vascular Biology
Aberrant angiogenesis in tumors can lead to the formation of blood vessels typically
characterized by highly disorganized and dilated architecture, excessive branching,
shunts and fenestrations, when compared to normal vessels (Marcucci and Corti
2011 ). Alteration of endothelial cell-cell adhesion and barrier function can lead to
heterogeneous permeability and increased interstitial fluid pressure (Marcucci and
Corti 2011 ). These structural and functional abnormalities of the vasculature may
contribute to tumor cell proliferation, migration, invasion, and metastasis formation
(Corti et al. 2011 ), and may also cause uneven penetration of drugs in tumors and
poor therapeutic responses (Marcucci and Corti 2011 ; Marcucci and Corti 2012 ).
Considering the vasoregulatory functions of CgA (discussed above) and the fact
that the tumor vasculature is exposed to CgA released in circulation by the neuroen-
docrine system and, in the case of neuroendocrine tumors, by the tumor cells them-
selves, it reasonable to hypothesize that CgA and its fragments may have a regulatory
F. Curnis et al.