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Regulation of tumor growth by circulating full-length chromogranin A

2016; Impact Journals LLC; Volume: 7; Issue: 45 Linguagem: Inglês

10.18632/oncotarget.12237

1949-2553

Flavio Curnis, Alice Dallatomasina, Mimma Bianco, Anna Maria Gasparri, Angelina Sacchi, Barbara Colombo, Martina Fiocchi, Laura Perani, Massimo Venturini, Carlo Tacchetti, Suvajit Sen, Ricardo Borges, Eleonora Dondossola, Antonio Esposito, Sushil K. Mahata, Angelo Corti,

Glycosylation and Glycoproteins Research

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.