TY - JOUR
T1 - Chromogranin a is preferentially cleaved into proangiogenic peptides in the bone marrow of multiple myeloma patients
AU - Bianco, Mimma
AU - Gasparri, Anna Maria
AU - Colombo, Barbara
AU - Curnis, Flavio
AU - Girlanda, Stefania
AU - Ponzoni, Maurilio
AU - Bertilaccio, Maria Teresa Sabrina
AU - Calcinotto, Arianna
AU - Sacchi, Angelina
AU - Ferrero, Elisabetta
AU - Ferrarini, Marina
AU - Chesi, Marta
AU - Bergsagel, P. Leif
AU - Bellone, Matteo
AU - Tonon, Giovanni
AU - Ciceri, Fabio
AU - Marcatti, Magda
AU - Caligaris-Cappio, Federico
AU - Corti, Angelo
N1 - Publisher Copyright:
© 2016 AACR. © 2016 American Association for Cancer Research.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N-and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk∗MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target.
AB - Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N-and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk∗MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target.
UR - http://www.scopus.com/inward/record.url?scp=84963743290&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84963743290&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-1637
DO - 10.1158/0008-5472.CAN-15-1637
M3 - Article
C2 - 26869462
AN - SCOPUS:84963743290
SN - 0008-5472
VL - 76
SP - 1781
EP - 1791
JO - Cancer research
JF - Cancer research
IS - 7
ER -