92
exogenous CgA can inhibit the in vivo penetration of an anti-Thy1.1 antibody into
lymphomas genetically engineered to express the Thy1.1 antigen, whereas the neu-
tralization of endogenous CgA with an anti-CgA antibody (mAb 5A8) promotes the
penetration of the anti-Thy1.1 antibody in the neoplastic tissues (Dondossola et al.
2012 ).
These observations rise the question as to whether the increased production of
CgA observed in certain cancer patients is good or bad. Increased expression of
CgA is associated with decreasing malignancy in neuroendocrine tumors, being
higher in well-differentiated carcinomas (low grade) and lower in poorly differenti-
ated (high grade) carcinomas (Helpap and Kollermann 2001 ). However, neuroendo-
crine differentiation in prostate tumors is associated with poorer prognosis (Young
et al. 2000 ) and large cell carcinomas of the lung with neuroendocrine features are
more clinically aggressive than classic large cell carcinomas (Iyoda et al. 2001 ).
Furthermore, CgA correlates with worsening conditions, extension of the disease,
and is an independent negative prognostic indicator of mortality in patients with non
small cell lung cancer (Gregorc et al. 2007 ). It is, therefore, very difficult to specu-
late on whether CgA is good or bad in patients based on these associations. The
overall biological effects of CgA likely dependent on its cellular source, its local
concentration, its proteolytic processing and its post-translational modifications,
which may vary from patient to patient. Possibly, while a regulated production and
processing of CgA is likely crucial for maintaining the vascular homeostasis in
physiological conditions, the unbalanced production of pro-/anti-angiogenic CgA
polypeptides observed in certain cancer patients may contribute to sustain angio-
genesis and tumor growth.
9 Conclusions
The experimental evidence accumulated so far suggests that circulating CgA and its
fragments contribute to the homeostatic regulation of blood vessels in normal con-
ditions and that alteration of their relative levels, either by changes in their secretion
or by proteolytic processing, might represent important mechanisms for angiogen-
esis activation and regulation. Considering that CgA is widely used as a serum
marker for various neoplastic and non-neoplastic diseases, selective quantification
of anti- and pro-angiogenic CgA-related polypeptides in plasma samples of patients
could represent an important step ahead for understanding the pathophysiological
significance of this protein and could provide important prognostic information in
cancer and other diseases with an angiogenesis component.
Acknowledgments This work was supported by Associazione Italiana per la Ricerca sul Cancro
(AIRC 14338 and 9965) of Italy.
F. Curnis et al.