Regulation of tumor growth by circulating full-length chromogranin A.
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.
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Flavio
F
Curnis
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Alice
A
Dallatomasina
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Mimma
M
Bianco
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Anna
A
Gasparri
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Angelina
A
Sacchi
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Barbara
B
Colombo
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Martina
M
Fiocchi
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Laura
L
Perani
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Massimo
M
Venturini
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Carlo
C
Tacchetti
University of California, Los Angeles, CA, USA.
Suvajit
S
Sen
La Laguna University, Tenerife, Spain.
Ricardo
R
Borges
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Eleonora
E
Dondossola
Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
Antonio
A
Esposito
VA San Diego Healthcare System and University of California, San Diego, La Jolla, CA, USA.
Sushil K
SK
Mahata
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
Angelo
A
Corti
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D045744:Cell Line, Tumor; D053379:Chromogranin A / Q000097:blood* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology; D011994:Recombinant Proteins; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D015415:Biomarkers; D053379:Chromogranin A; D010446:Peptide Fragments; D011994:Recombinant Proteins; D058258:Serpin E2
angiogenesis; chromogranin A; endothelial cells; protease-nexin-1; tumor perfusion
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