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

Vascular endothelial growth factor165 (VEGF165) and semaphorin3A (SEMA3A) elicit pro- and anti-angiogenic signals respectively in endothelial cells (EC) by binding to their receptors VEGFR-2, neuropilin-1 (Nrp- 1), and plexin-A1. Here we show that the VEGF165-driven angiogenic potential of multiple myeloma (MM) EC is significantly higher than that of monoclonal gammopathy of undetermined significance (MGUS) EC (MGEC) and human umbilical vein (HUV) EC. This is probably due to a constitutive imbalance of endogenous VEGF165/SEMA3A ratio, which leans on VEGF165 in MMEC but on SEMA3A in MGEC and HUVEC. Exogenous VEGF165 induces SEMA3A expression in MGEC and HUVEC, but not in MMEC. Moreover, by counteracting VEGF165 activity as efficiently as an anti-VEGFR-2 antibody, exogenous SEMA3A restrains the over-angiogenic potential of MMEC. Our data indicate that loss of endothelial SEMA3A in favor of VEGF165 could be responsible for the angiogenic switch from MGUS to MM.