IntroductionMultiple myeloma (MM) remains an incurable disease, despite conventional and high-dose chemotherapies. 1 Molecules targeting not only plasma cells, but also the bone marrow (BM) microenvironment are needed to overcome drug resistance.Pathologic angiogenesis is a constant component of the MM microenvironment. 2 The vascular endothelial growth factor (VEGF)/ VEGF receptor-2 (VEGFR-2) pathway greatly contributes to MM angiogenesis and growth, 3 and mediates proliferation and capillarogenesis in MM endothelial cells (MMECs) through an autocrine loop. 4 VEGF 165 is the most abundant and effective isoform. 5 It binds simultaneously to its cognate receptors VEGFR-1 and VEGFR-2 and to the coreceptor neuropilin-1 (NRP1), a cellsurface glycoprotein expressed on axons in the developing nervous system as well. 6 NRP1 is the ligand-binding subunit of the receptor complex for class 3 semaphorins, a family of secreted proteins that mediate neuronal guidance. 7 Binding of secreted semaphorin 3A (SEMA3A) to NRP1 induces the collapse of neuronal growth cones 8 by activating the signal-transducing subunit(s) of the receptor complex, that is, class A plexins, a family of transmembrane proteins whose cytoplasmic domain is endowed with an R-Ras GAP activity that inhibits integrin function. 9 NRP1 is also expressed on ECs, 10 where it acts as an isoform-specific receptor for VEGF 165 , and enhances by 4-to 6-fold its affinity for VEGFR-2, as well as VEGF 165 -induced cell chemotaxis and proliferation. 11 By competing with VEGF 165 for binding to NRP1 12 and by activating class A plexins, 13 SEMA3A inhibits integrinbased EC adhesion and migration and capillary sprouting. Autocrine loops of endothelial SEMA3A play a self-limiting role in angiogenesis and regulate EC behavior during its physiologic development. 13 Here we analyze the expression levels of VEGF 165 , SEMA3A, and their receptors NRP1 and plexin-A1 in BM ECs isolated from patients with MM and MGUS (MMECs and MGECs), and from the human umbilical vein (HUVECs). We show that overangiogenic MMECs display a high VEGF 165 /SEMA3A ratio and behave like MGECs and HUVECs upon exposure to exogenous SEMA3A, which seems as effective as an anti-VEGFR-2 antibody. Our observations point to SEMA3A as a potential antiangiogenic Patients, materials, and methods PatientsThirty-two patients fulfilling the International Myeloma Working Group diagnostic criteria 14 for MM (n ϭ 18) and MGUS (n ϭ 14) were studied at diagnosis. The MM patients (12 male, 6 female) were aged 44 to 81 years (median 68.5 years) and staged 15 as IIA (n ϭ 4), IIB (n ϭ 2), IIIA (n ϭ 10), and IIIB (n ϭ 2); the M-component was IgG (n ϭ 12), IgA (n ϭ 4), and or (n ϭ 2). The MGUS patients (8 male, 6 female) were aged 42 to 79 years (median 70.6 years) and were IgG (n ϭ 10) or IgA (n ϭ 4). The study was approved by the local ethics committee of the University of Bari Medical School, Italy, and all patients gave their informed consent in accordance with the Declaration of Helsinki. Separation and culture of ECs and...
Cytoskeleton-toxic chemotherapeuticals, such as vinblastine and paclitaxel, display antiangiogenic activity. This study was designed to compare paclitaxel to its analog docetaxel and assess their doses still antiangiogenic in vitro and in vivo. Human endothelial cell functions involved in angiogenesis, namely proliferation, chemotaxis, morphogenesis, and secretion of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA) were studied in vitro upon exposure to docetaxel and paclitaxel, whereas their effect on angiogenesis was studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. Proliferation of mouse embryo fibroblasts and human Kaposi's sarcoma, breast and endometrial carcinoma, and lymphoid tumor cells was also studied. In vitro, 0.5, 0.75, and 1 nM docetaxel and 2, 3, and 4 nM paclitaxel, i.e., non-cytotoxic doses, impacted all endothelial cell functions, but not protease secretion, in a dose-dependent fashion, whereas they did not affect the proliferation of other cells, except those of Kaposi's sarcoma. No apoptosis was induced by 0.5 nM docetaxel and 2 nM paclitaxel, and moderate apoptosis was induced by 1 nM docetaxel and 4 nM paclitaxel. The antiangiogenic effect rapidly disappeared on drug suspension and was accompanied ultrastructurally by thin lesions of cytoskeleton in the form of slight and equally reversible depolymerization and accumulation of microfilaments. Massive endothelial cell apoptosis with evident cytotoxicity and irreversibility were associated with 2 nM docetaxel and 5 nM paclitaxel, although these higher doses were ineffective on other cells except Kaposi's sarcoma cells. In vivo, 1, 2, and 3 nM docetaxel and 4, 8, and 12 nM paclitaxel displayed a dose-dependent antiangiogenic activity. We suggest that very low docetaxel and paclitaxel doses selectively cause organic and functional damage of endothelial cells and that docetaxel is four times stronger. Their antiangiogenic activity could be applied to treat Kaposi's sarcoma and cancers.
Multiple myeloma (MM) progresses from an avascular to a vascular phase (active MM) accompanied by a significant increase in microvessel density in the bone marrow. This article summarizes the literature concerning the specific role played by vascular endothelial growth factor (VEGF) in this process. Recent applications of antiangiogenic agents that interfere with VEGF signaling and block MM progression are also described.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.