Relationship between survival and edema in malignant gliomas: role of vascular endothelial growth factor and neuronal pentraxin 2.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood.


METHODS
Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival.


CONCLUSIONS
VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P<0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P<0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P=0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P<0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.
Carlson
Marc R J
MR
Department of Human Genetics, University of California at Los Angeles and David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California 90095-1271, USA.
Pope
Whitney B
WB
Horvath
Steve
S
Braunstein
Jerome G
JG
Nghiemphu
Phioanh
P
Tso
Cho-Lea
CL
Mellinghoff
Ingo
I
Lai
Albert
A
Liau
Linda M
LM
Mischel
Paul S
PS
Dong
Jun
J
Nelson
Stanley F
SF
Cloughesy
Timothy F
TF
D053607:Adrenomedullin / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D051400:Aquaporin 3 / Q000235:genetics; D001929:Brain Edema / Q000175:diagnosis* / Q000235:genetics; D001932:Brain Neoplasms / Q000150:complications / Q000401:mortality*; D002097:C-Reactive Protein / Q000235:genetics*; D015870:Gene Expression; D005910:Glioma / Q000150:complications / Q000401:mortality*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D013534:Survival; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D000099153:Pentraxins
D053607:Adrenomedullin; D042702:Angiopoietin-2; D051400:Aquaporin 3; D002097:C-Reactive Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D042461:Vascular Endothelial Growth Factor A; D000099153:Pentraxins