Chromogranin a is preferentially cleaved into proangiogenic peptides in the bone marrow of multiple myeloma patients

Mimma Bianco, Anna Maria Gasparri, Barbara Colombo, Flavio Curnis, Stefania Girlanda, Maurilio Ponzoni, Maria Teresa Sabrina Bertilaccio, Arianna Calcinotto, Angelina Sacchi, Elisabetta Ferrero, Marina Ferrarini, Marta Chesi, P. Leif Bergsagel, Matteo Bellone, Giovanni Tonon, Fabio Ciceri, Magda Marcatti, Federico Caligaris-Cappio, Angelo Corti

Research output: Contribution to journalArticle

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 VkMYC 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.

Original languageEnglish
Pages (from-to)1781-1791
Number of pages11
JournalCancer Research
Volume76
Issue number7
DOIs
Publication statusPublished - Apr 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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