*2.3. Potential Therapeutic Applications of Compounds That Interfere with CgA Fragment/ Neuropilin-1 Interaction*

The unbalanced production of anti- and pro-angiogenic factors in tumor tissues can trigger aberrant angiogenesis and altered vascular morphology, which, in turn, may contribute to tumor cell proliferation, invasion, trafficking and formation of metastases [54–56]. The studies performed in patients with multiple myeloma have shown that CgA is cleaved into the proangiogenic form CgA1-373 in the bone marrow and that, consequently, the ratio of pro-/anti-angiogenic forms of CgA is higher in patients compared to healthy individuals [43]. Enhanced CgA cleavage correlated with increased levels of vascular endothelial growth factor and fibroblast growth factor-2 in the bone marrow plasma, and with an increased bone marrow microvascular density [43]. Studies on the mechanism of action revealed that multiple myeloma and endothelial cells can promote CgA cleavage through the activation of the plasminogen activator/plasmin system [43].

Other studies aimed at evaluating the extent and prognostic value of CgA cleavage in patients with pancreatic ductal adenocarcinoma, an aggressive cancer arising from the exocrine component of the pancreas [57–59], have shown that cleavage of the R373R374 bond and of other sites in the C-terminal region of circulating CgA is increased in these patients. Remarkably, CgA cleavage predicts progression-free survival and overall survival in these cancer patients [38]. Experimental evidence, obtained using various pre-clinical models of pancreatic ductal adenocarcinoma, suggests that the plasminogen activator/plasmin system has a role in CgA processing in this case, and that CgA cleavage has a functional role of in the regulation of tumor vascular biology. Remarkably, anti-PGPQLR373 antibodies capable of blocking the binding of CgA1-373 to neuropilin-1 can reduce the growth of pancreatic ductal adenocarcinoma in mice, which implicates an important role of neuropilin-1 as mediator of these effects [38].

As cleavage of plasma CgA in tumors and the consequent interaction with neuropilin-1 may represent an important mechanism for the regulation of tumor vascular biology and growth, the assessment of the extent of CgA fragmentation in cancer patients may have a prognostic value, whereas the development of compounds that target and block this ligand-receptor interaction (e.g., anti-PGPQLR373 monoclonal antibodies) may have a therapeutic value (see Figure 1B for a schematic representation of this concept).
