Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma

Vascular endothelial growth factor(165) (VEGF(165)) and semaphorin3A (SEMA3A) elicit pro- and antiangiogenic signals respectively in endothelial cells (ECs) by binding to their receptors VEGFR-2, neuropilin-1 (NRP1), and plexin-All. Here we show that the VEGF(165)-driven angiogenic potential of multiple myeloma (MM) ECs is significantly higher than that of monoclonal gammopathy of undetermined significance (MGUS) ECs (MGECs) and human umbilical vein (HUV) ECs. This is probably due to a constitutive imbalance of endogenous VEGF(165)/SEMA3A ratio, which leans on VEGF(165) in MMECs but on SEMA3A in MGECs and HUVECs. Exogenous VEGF(165) induces SEMA3A expression in MGECs and HUVECs, but not in MMECs. Moreover, by counteracting VEGF(165) activity as efficiently as an anti-VEGFR-2 antibody, exogenous SEMA3A restrains the over-angiogenic potential of MMECs. Our data indicate that loss of endothelial SEMA3A in favor of VEGF(165) could be responsible for the angiogenic switch from MGUS to MM.