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.
Highlights
Human chromogranin A (CgA) is a 439 residuelong protein stored in the dense-core granules of many neuroendocrine cells and neurons, and exocytotically released into the blood to reach about 0.5 nM levels [1, 2]
We show that full-length CgA can impair angiogenesis, tumor perfusion and tumor growth through mechanisms depending on the induction of protease nexin-1, a serine protease inhibitor endowed of anti-angiogenic activity
The results show that full-length CgA, a protein released in circulation by the neuroendocrine system, can regulate the growth of solid tumors
Summary
Human chromogranin A (CgA) is a 439 residuelong protein stored in the dense-core granules of many neuroendocrine cells and neurons, and exocytotically released into the blood to reach about 0.5 nM levels [1, 2]. Increased levels of CgA have been immunologically www.impactjournals.com/oncotarget detected in the blood of patients with neuroendocrine tumors or with tumors that undergo neuroendocrine differentiation, including prostate, breast and non-small cell lung cancer [2, 6,7,8]. For these reasons CgA is widely used as a serological marker for neuroendocrine tumor diagnosis or for monitoring tumor progression/regression after therapy. Variable levels of full-length CgA and fragments are present in the blood of cancer patients for a variety of reasons
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