Abstract
Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis. In vitro studies showed that PDAC cells can promote the cleavage of CgA C-terminal region by activating plasminogen to plasmin. Limited digestion of full-length CgA with plasmin abolished its anti-angiogenic activity and generated pro-angiogenic molecules. The fragmentation of CgA C-terminal region was increased also in murine models of PDAC. In these models, the inhibition of CgA fragmentation with aprotinin, an inhibitor of plasmin and other serine proteases, or the blockade of pro-angiogenic fragments with specific antibodies inhibited the growth of PDAC implanted subcutaneously in mice. Finally, administration of full-length CgA to mice bearing orthotopic PDAC reduced tumor perfusion, as measured by contrast-enhanced ultrasound. These findings suggest that PDAC can promote the cleavage of circulating CgA C-terminal region to generate fragments that regulate the tumor vascular biology and that may represent new potential therapeutic targets.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is an aggressive malignancy arising from the exocrine epithelial component of the pancreas [1]
Using in vitro and in vivo models of PDAC, we provide data suggesting a role of the plasminogen activator-plasmin system in chromogranin A (CgA) cleavage and a function of CgA fragmentation in the regulation of PDAC vascular biology
The results show that the N-terminal fragment CgA1-76 was present in the blood of healthy subjects, suggesting that partial cleavage of CgA N- and C-terminal regions occurs in healthy conditions
Summary
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is an aggressive malignancy arising from the exocrine epithelial component of the pancreas [1]. A growing body of evidence suggests that circulating chromogranin A (CgA), an acidic secretory protein, may represent an important regulating factor of the vascular biology of solid tumors [5,6,7,8]. CgA1-439 and some of its fragments (e.g., vasostatin-1, catestatin and serpinin) can exert a variety of biological functions in the regulation of cardiovascular system, metabolism and innate immunity [13] Regarding their vascular functions, recent studies have shown that CgA1-439 can exert anti-angiogenic effects at physiological concentrations [5, 6, 8]. Cleavage of circulating CgA in tumors and in the blood may represent a complex mechanism for the spatio-temporal regulation of the tumor vascular biology According to this view, a significant correlation between CgA fragmentation at the R373-R374 site and tumor microvessel density has been observed in the bone marrow of patients with multiple myeloma [12]. Using in vitro and in vivo models of PDAC, we provide data suggesting a role of the plasminogen activator-plasmin system in CgA cleavage and a function of CgA fragmentation in the regulation of PDAC vascular biology
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