title: Chromogranin A Is Preferentially Cleaved into Proangiogenic Peptides in the Bone Marrow of Multiple Myeloma Patients.
abstract: 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. Cancer Res; 76(7); 1781-91. ©2016 AACR.
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Mimma
authors: M
authors: Bianco
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Anna Maria
authors: AM
authors: Gasparri
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Barbara
authors: B
authors: Colombo
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Flavio
authors: F
authors: Curnis
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Stefania
authors: S
authors: Girlanda
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Maurilio
authors: M
authors: Ponzoni
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Maria Teresa Sabrina
authors: MT
authors: Bertilaccio
authors: Division of Immunology, San Raffaele Scientific Institute, Milan, Italy.
authors: Arianna
authors: A
authors: Calcinotto
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Angelina
authors: A
authors: Sacchi
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Elisabetta
authors: E
authors: Ferrero
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Marina
authors: M
authors: Ferrarini
authors: Mayo Clinic, Scottsdale, Arizona.
authors: Marta
authors: M
authors: Chesi
authors: Mayo Clinic, Scottsdale, Arizona.
authors: P Leif
authors: PL
authors: Bergsagel
authors: Division of Immunology, San Raffaele Scientific Institute, Milan, Italy.
authors: Matteo
authors: M
authors: Bellone
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Giovanni
authors: G
authors: Tonon
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Fabio
authors: F
authors: Ciceri
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors: Magda
authors: M
authors: Marcatti
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy. Università Vita-Salute San Raffaele, Milan, Italy.
authors: Federico
authors: F
authors: Caligaris-Cappio
authors: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy. Università Vita-Salute San Raffaele, Milan, Italy. corti.angelo@hsr.it.
authors: Angelo
authors: A
authors: Corti
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D053379:Chromogranin A / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic; D010455:Peptides / Q000235:genetics*
chemical_list: D053379:Chromogranin A; D010455:Peptides