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Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma

Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastati...

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Autores principales: Reni, Michele, Andreasi, Valentina, Gasparri, Anna Maria, Dugnani, Erica, Colombo, Barbara, Macchini, Marina, Bianco, Mimma, Dallatomasina, Alice, Citro, Antonio, Assi, Emma, Protti, Maria Pia, Esposito, Antonio, Falconi, Massimo, Curnis, Flavio, Piemonti, Lorenzo, Corti, Angelo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787052/
https://www.ncbi.nlm.nih.gov/pubmed/33425767
http://dx.doi.org/10.3389/fonc.2020.613582
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author Reni, Michele
Andreasi, Valentina
Gasparri, Anna Maria
Dugnani, Erica
Colombo, Barbara
Macchini, Marina
Bianco, Mimma
Dallatomasina, Alice
Citro, Antonio
Assi, Emma
Protti, Maria Pia
Esposito, Antonio
Falconi, Massimo
Curnis, Flavio
Piemonti, Lorenzo
Corti, Angelo
author_facet Reni, Michele
Andreasi, Valentina
Gasparri, Anna Maria
Dugnani, Erica
Colombo, Barbara
Macchini, Marina
Bianco, Mimma
Dallatomasina, Alice
Citro, Antonio
Assi, Emma
Protti, Maria Pia
Esposito, Antonio
Falconi, Massimo
Curnis, Flavio
Piemonti, Lorenzo
Corti, Angelo
author_sort Reni, Michele
collection PubMed
description Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis. In vitro studies showed that PDAC cells can promote the cleavage of CgA C-terminal region by activating plasminogen to plasmin. Limited digestion of full-length CgA with plasmin abolished its anti-angiogenic activity and generated pro-angiogenic molecules. The fragmentation of CgA C-terminal region was increased also in murine models of PDAC. In these models, the inhibition of CgA fragmentation with aprotinin, an inhibitor of plasmin and other serine proteases, or the blockade of pro-angiogenic fragments with specific antibodies inhibited the growth of PDAC implanted subcutaneously in mice. Finally, administration of full-length CgA to mice bearing orthotopic PDAC reduced tumor perfusion, as measured by contrast-enhanced ultrasound. These findings suggest that PDAC can promote the cleavage of circulating CgA C-terminal region to generate fragments that regulate the tumor vascular biology and that may represent new potential therapeutic targets.
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spelling pubmed-77870522021-01-07 Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma Reni, Michele Andreasi, Valentina Gasparri, Anna Maria Dugnani, Erica Colombo, Barbara Macchini, Marina Bianco, Mimma Dallatomasina, Alice Citro, Antonio Assi, Emma Protti, Maria Pia Esposito, Antonio Falconi, Massimo Curnis, Flavio Piemonti, Lorenzo Corti, Angelo Front Oncol Oncology Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis. In vitro studies showed that PDAC cells can promote the cleavage of CgA C-terminal region by activating plasminogen to plasmin. Limited digestion of full-length CgA with plasmin abolished its anti-angiogenic activity and generated pro-angiogenic molecules. The fragmentation of CgA C-terminal region was increased also in murine models of PDAC. In these models, the inhibition of CgA fragmentation with aprotinin, an inhibitor of plasmin and other serine proteases, or the blockade of pro-angiogenic fragments with specific antibodies inhibited the growth of PDAC implanted subcutaneously in mice. Finally, administration of full-length CgA to mice bearing orthotopic PDAC reduced tumor perfusion, as measured by contrast-enhanced ultrasound. These findings suggest that PDAC can promote the cleavage of circulating CgA C-terminal region to generate fragments that regulate the tumor vascular biology and that may represent new potential therapeutic targets. Frontiers Media S.A. 2020-12-23 /pmc/articles/PMC7787052/ /pubmed/33425767 http://dx.doi.org/10.3389/fonc.2020.613582 Text en Copyright © 2020 Reni, Andreasi, Gasparri, Dugnani, Colombo, Macchini, Bianco, Dallatomasina, Citro, Assi, Protti, Esposito, Falconi, Curnis, Piemonti and Corti http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Reni, Michele
Andreasi, Valentina
Gasparri, Anna Maria
Dugnani, Erica
Colombo, Barbara
Macchini, Marina
Bianco, Mimma
Dallatomasina, Alice
Citro, Antonio
Assi, Emma
Protti, Maria Pia
Esposito, Antonio
Falconi, Massimo
Curnis, Flavio
Piemonti, Lorenzo
Corti, Angelo
Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title_full Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title_fullStr Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title_full_unstemmed Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title_short Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma
title_sort circulating chromogranin a is cleaved into vasoregulatory fragments in patients with pancreatic ductal adenocarcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787052/
https://www.ncbi.nlm.nih.gov/pubmed/33425767
http://dx.doi.org/10.3389/fonc.2020.613582
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