High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas.
Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. Neuroblastoma (NB) is a common pediatric tumor of neural crest origin, which is biologically and clinically heterogeneous. Increased tumor vascular index correlates with poor outcome of NB. To determine which angiogenic factors contribute to NB angiogenesis and thereby support tumor progression, we examined the expression of eight angiogenic factors [vascular endothelial growth factor (VEGF), VEGF-B, VEGF-C, basic fibroblast growth factor, angiopoietin (Ang)-1, Ang-2, transforming growth factor alpha, and platelet-derived growth factor (PDGF)] by semiquantitative RT-PCR in 37 NB primary tumors and in 22 NB cell lines. We also analyzed the relationship between angiogenic factor expression and clinicopathological factors as well as patient survival. All eight angiogenic factors examined were expressed at various levels in NB cell lines and tumors, suggesting their involvement in NB angiogenesis. The expression levels of most angiogenic factors were correlated with each other, suggesting their synergy in regulating the angiogenic process. Significantly higher expression levels of VEGF, VEGF-B, VEGF-C, basic fibroblast growth factor, Ang-2, transforming growth factor alpha, and PDGF-A (P < 0.0001-0.026) were found in advanced-stage tumors (stages 3 and 4) compared with low-stage tumors (stages 1, 2, and 4S). Expression of PDGF-A was significantly associated with patient survival (P = 0.04). The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB.
Eggert
A
A
Division of Oncology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. eggert@emailchop.edu
Ikegaki
N
N
Kwiatkowski
J
J
Zhao
H
H
Brodeur
G M
GM
Himelstein
B P
BP
D043925:Angiogenesis Inducing Agents / Q000235:genetics*; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D002648:Child; D002675:Child, Preschool; D016228:Endothelial Growth Factors / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D007223:Infant; D008222:Lymphokines / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D042582:Vascular Endothelial Growth Factor C; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D020917:Receptor, trkA