TY - JOUR
T1 - Regulation of tumor growth by circulating full-length chromogranin A
AU - Curnis, Flavio
AU - Dallatomasina, Alice
AU - Bianco, Mimma
AU - Gasparri, Anna
AU - Sacchi, Angelina
AU - Colombo, Barbara
AU - Fiocchi, Martina
AU - Perani, Laura
AU - Venturini, Massimo
AU - Tacchetti, Carlo
AU - Sen, Suvajit
AU - Borges, Ricardo
AU - Dondossola, Eleonora
AU - Esposito, Antonio
AU - Mahata, Sushil K.
AU - Corti, Angelo
N1 - Funding Information:
TEM studies were carried out at the TEM Core Facility at the University of California, San Diego. We thank Sumana Mahata for editing the manuscript This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC, Special Program Molecular Clinical Oncology 5x1000-9965 and IG-14338). S.K.M. is supported by the VA Research Career Scientist Award.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Chromogranin A
KW - Endothelial cells
KW - Protease-nexin-1
KW - Tumor perfusion
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U2 - 10.18632/oncotarget.12237
DO - 10.18632/oncotarget.12237
M3 - Article
C2 - 27683038
AN - SCOPUS:84995792987
SN - 1949-2553
VL - 7
SP - 72716
EP - 72732
JO - Oncotarget
JF - Oncotarget
IS - 45
ER -