Hypoxia and activated VEGF/receptor pathway in multiple myeloma.
OBJECTIVE
Intensified angiogenic pathways are associated with poor prognosis and resistance of multiple myeloma (MM) cells to therapy. The links of the VEGF pathway with the hypoxia inducible factor (HIF) expression in MM are herein investigated.


METHODS
The vascular density (VD) and the HIF/VEGF/VEGF-receptor expression in the bone marrows of 106 MM cases were studied using immunohistochemistry.


RESULTS
HIF1alpha and HIF2alpha were expressed strongly in 33% and 13.2% of the cases, respectively. VEGFR and the phosphorylated (active) form of VEGFR2/KDR receptors were up-regulated in 42.5% and 36.8% of cases, respectively. Both HIF1alpha and HIF2alpha were significantly linked with high VD and VEGF expression. Moreover, the expression of the phosphorylated (active) form of VEGFR2/KDR was significantly linked with VEGF and HIF1alpha expression. The HIF/VEGF/VEGF-receptor pathway is up-regulated in approximately 40% of MM cases and linked with increased angiogenesis. Survival analysis in 37 evaluable patients showed a significantly worse prognosis in cases with high VD.


CONCLUSIONS
HIFs and VEGF are up-regulated in a significant percentage of MM and are strongly related to each other. Targeting HIFs and the VEGF/receptor autocrine loop may prove of importance in the treatment of the disease.
Giatromanolaki
Alexandra
A
Department of Pathology, Democritus University of Thrace, P.O. Box 12, Alexandroupolis 68100, Greece. targ@her.forthnet.gr
Bai
Maria
M
Margaritis
Dimitrios
D
Bourantas
Konstantinos L
KL
Koukourakis
Michael I
MI
Sivridis
Efthimios
E
Gatter
Kevin C
KC
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D009101:Multiple Myeloma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C467484:VEGFA protein, human