Chromogranin A is preferentially cleaved into pro-angiogenic peptides in the bone marrow of multiple myeloma patients

Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma (MM), 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 anti-angiogenic protein, can activate latent anti- and pro-angiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in MM patients and the subsequent implications for disease progression. We show that the ratio of pro-/anti-angiogenic forms of CgA is altered in MM 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 MM, we further demonstrate that exogenously administered CgA was cleaved in favor of the pro-angiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that MM 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-/anti-angiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of MM patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target.

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