Regulation of tumor growth by circulating full-length chromogranin A

Abstract

Chromogranin A (CgA), a neuroendocrine secretory protein, and its fragments are present in variable amounts in the blood of normal subjects and cancer patients. We investigated whether circulating CgA has a regulatory function in tumor biology and progression. Systemic administration of full-length CgA, but not of fragments lacking the C-terminal region, could reduce tumor growth in murine models of fibrosarcoma, mammary adenocarcinoma, Lewis lung carcinoma, and primary and metastatic melanoma, with U-shaped dose-response curves. Tumor growth inhibition was associated with reduction of microvessel density and blood flow in neoplastic tissues. Neutralization of endogenous CgA with antibodies against its C-terminal region (residues 410-439) promoted tumor growth. Structure-function studies showed that the C-terminal region of CgA contains a bioactive site and that cleavage of this region causes a marked loss of anti-angiogenic and anti-tumor potency. Mechanistic studies showed that full-length CgA could induce, with a U-shaped dose-response curve, the production of protease nexin-1 in endothelial cells, a serine protease inhibitor endowed of anti-angiogenic activity. Gene silencing or neutralization of protease nexin-1 with specific antibodies abolished both anti-angiogenic and anti-tumor effects of CgA. These results suggest that circulating full-length CgA is an important inhibitor of angiogenesis and tumor growth, and that cleavage of its C-terminal region markedly reduces its activity. Pathophysiological changes in CgA blood levels and/or its fragmentation might regulate disease progression in cancer patients.

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

“…Of note, CgA alone could also delay tumor growth in some models. This was not unexpected because we have previously shown that CgA can inhibit tumor growth by inhibiting angiogenesis (31).…”

“…An important point that deserves to be discussed is that the protective activity was obtained with a dose of exogenous CgA that generates 2-4 nM peak plasma levels [i.e., within the 2-5 nM range of physiologic levels of CgA observed in untreated rats (31)]. These findings suggest that endogenous CgA at concentrations close to normal physiologic values have a significant role in cardioprotection.…”

“…The cardiotoxic cumulative dose of Doxo, pharmacologically scaled for rats, corresponds to that used in human patients (28)(29)(30). This dose of CgA (;0.2 nmol/kg/d) generates physiologically relevant plasma levels of CgA (31).…”

Spatiotemporal Regulation of Tumor Angiogenesis by Circulating Chromogranin A Cleavage and Neuropilin-1 Engagement

“…Contrast-enhanced ultrasound (CEUS) analysis was performed using a high-performance ultrasonographic scanner designed for small-animal imaging (Vevo 2100; Visual Sonics) as described previously (11,26).…”

“…Abnormal levels of immunoreactive CgA have been detected in the blood of patients with neuroendocrine tumors and in several other pathologic conditions, including nonneuroendocrine tumors and cardiovascular, gastrointestinal, renal, and inflammatory disorders (8)(9)(10). Recent studies have shown that full-length CgA (CgA 1-439 ) can regulate the endothelial barrier function, exert antiangiogenic effects at physiologic concentrations, and inhibit tumor growth in various animal models (11)(12)(13). A functional antiangiogenic site is located in the C-terminal region 410-439 and a latent (or less active) site is present in the N-terminal region 1-76, this site requiring proteolytic cleavage for full activation (12).…”