A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma.
OBJECTIVE
In tumors, vascular endothelial growth factor-A (VEGF-A) stimulates angiogenesis and vascular permeability by activating the tyrosine kinase receptor-2 (VEGFR-2 or KDR/Flk-1) and-1 (VEGFR-1 or Flt-1).


METHODS
The distribution and function of VEGF homologs and their receptors on bone marrow plasma cells, endothelial cells, and other stromal cells (residual stromal cells) were examined in patients with multiple myeloma (MM).


RESULTS
Plasma cells secrete VEGF-A (and VEGF-B, VEGF-C and VEGF-D, albeit marginally) into their conditioned medium (CM). CM VEGF-A stimulates proliferation and chemotaxis in endothelial cells (both being mandatory for angiogenesis) via VEGF receptor-2 (VEGFR-2), and in residual stromal cells via the VEGFR-1. Residual stromal cells secrete VEGF-C and VEGF-D, but little of the other homologs. Their CM VEGF-C and VEGF-D increase in response to plasma cell CM and trigger plasma cell proliferation via VEGFR-3. Proliferation in all cell types parallels VEGFR and extracellular signal-regulated protein kinase-2 (ERK-2) phosphorylation. The homologs and receptors are weakly or inconstantly expressed in patients with monoclonal gammopathies of undetermined significance or vitamin B12/iron deficiency anemias.


CONCLUSIONS
This study shows that the VEGF pathway is directly involved in tumor angiogenesis and growth in MM. A paracrine VEGF loop for MM progression is suggested. This, in turn, provides a further indication that the VEGF pathway and its signaling proteins may be appropriate targets in the management of MM.
Vacca
Angelo
A
Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Italy. avacca@dimo.uniba.it
Ria
Roberto
R
Ribatti
Domenico
D
Semeraro
Fabrizio
F
Djonov
Valentin
V
Di Raimondo
Francesco
F
Dammacco
Franco
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor