A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma

Thromb Haemost. 2004 Dec;92(6):1438-45. doi: 10.1160/TH04-06-0334.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Blotting, Western
  • Bone Marrow Cells / cytology*
  • Capillaries / metabolism
  • Cell Proliferation
  • Collagen / metabolism
  • Collagen / pharmacology
  • Culture Media, Conditioned / pharmacology
  • Culture Media, Serum-Free / pharmacology
  • Drug Combinations
  • Endothelium, Vascular / cytology*
  • Female
  • Humans
  • Laminin / metabolism
  • Laminin / pharmacology
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Multiple Myeloma / pathology*
  • Neovascularization, Pathologic
  • Phosphorylation
  • Proteoglycans / metabolism
  • Proteoglycans / pharmacology
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Umbilical Veins / cytology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Culture Media, Conditioned
  • Culture Media, Serum-Free
  • Drug Combinations
  • Laminin
  • Proteoglycans
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • matrigel
  • Collagen
  • Vascular Endothelial Growth Factor Receptor-2
  • Mitogen-Activated Protein Kinase 1