Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors.
BACKGROUND
Vascular endothelial growth factor (VEGF) is a critical proangiogenic factor in solid tumors. However, its expression and role in human neuroendocrine tumor development and progression remains unclear.


METHODS
Using immunohistochemistry, VEGF and Sp1 expression patterns were investigated in 50 cases of human gastrointestinal neuroendocrine tumor having various clinicopathologic characteristics.


RESULTS
It was found that strong VEGF expression was detected in tumor cells, whereas no or very weak VEGF expression was detected in stromal cells surrounding or within the tumors. The levels of VEGF expression directly correlated with the expression levels of Sp1 and microvessel density. Strong, weak, and negative VEGF expression was observed in 32%, 54%, and 14% of cases, respectively. Compared with the group with negative VEGF expression, VEGF (weak/strong) expression was associated with metastasis (14% versus 58%; P = .03). The median progression-free survival (PFS) durations of patients with strong and weak VEGF expression were 29 months and 81 months, respectively. With a median follow-up duration of 50 months, the median PFS duration for the group with negative VEGF expression has not been reached. Compared with the log-rank test, VEGF expression was associated with poor PFS (P = .02). Using in vitro and in vivo models, human carcinoid cell lines were treated with bevacizumab, a monoclonal antibody targeting VEGF. Bevacizumab did not inhibit the growth of carcinoid cells in vitro but significantly reduced tumor angiogenesis and impaired tumor growth in animals.


CONCLUSIONS
The data suggest that overexpression of VEGF promotes the growth of human neuroendocrine tumors in part through up-regulation of angiogenesis.
Zhang
Jun
J
Department of Gastrointestinal Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Jia
Zhiliang
Z
Li
Qiang
Q
Wang
Liwei
L
Rashid
Asif
A
Zhu
Zhenggang
Z
Evans
Douglas B
DB
Vauthey
Jean-Nicolas
JN
Xie
Keping
K
Yao
James C
JC
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D018278:Carcinoma, Neuroendocrine / Q000098:blood supply* / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab