A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma.
The expression/function of vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2/KDR) in multiple myeloma (MM)-associated angiogenesis is under scrutiny. We show here that bone marrow endothelial cells (EC) from 16 patients with MM (MMEC) highly expressed VEGF-A (the main VEGF isoform) and VEGFR-2 at both mRNA and protein level, whereas EC from 14 patients with monoclonal gammopathy unassociated/unattributable (MG[u]) (MG[u]EC) and 12 human umbilical veins (HUVEC) expressed very low mRNAs and/or proteins. MMEC showed constitutive autophosphorylation in both VEGFR-2 and the associated extracellular signal-regulated kinase-2 (ERK-2), whereas this was marginal in MG[u]EC and HUVEC. MMEC proliferated rapidly and formed a closely-knit capillary meshwork on Matrigel. These cell functions were reduced in the other EC. Autophosphorylation, proliferation and capillarogenesis were prevented by a neutralizing anti-VEGF-A antibody, and more efficaciously by an anti-VEGFR-2 antibody. Both antibodies had no effect or were poorly effective on the other EC. These findings as a whole suggest the existence of an autocrine loop of VEGF in MMEC. Since this is very likely a mechanism for the amplification of VEGF activity in neovascularization, it would constitute an appropriate target for antiangiogenic management in MM.
Ria
Roberto
R
Department of Internal Medicine and Clinical Oncology, Piazza Giulio Cesare, 11, Policlinico, I-70124, Bari, Italy.
Vacca
Angelo
A
Russo
Francesca
F
Cirulli
Teresa
T
Massaia
Massimo
M
Tosi
Patrizia
P
Cavo
Michele
M
Guidolin
Diego
D
Ribatti
Domenico
D
Dammacco
Franco
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D002196:Capillaries / Q000378:metabolism; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D017077:Culture Media, Conditioned; D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1