Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer.
OBJECTIVE
Vascular endothelial growth factor has a critical role in maintaining tumor microvasculature and, as such, is an attractive target for anti-angiogenic therapy. Aberrant expression of VEGF receptors, especially VEGFR2, on epithelial tumor cells allows VEGF to stimulate growth and migration of tumor cells in an autocrine and/or paracrine manner. Therefore, we studied the expression of VEGF and VEGFR2 in bladder cancer, and the relationship to disease characteristics.


METHODS
Expression of VEGF and VEGFR2 was studied in a cohort of 72 patients with transitional cell cancer of the bladder. Tumor tissues from all patients were analyzed by immunohistochemistry and examined by a pathologist blinded to patient outcome. Patient demographics and disease outcome were correlated with expression of these markers. Bladder cancer cell lines that express VEGFR2 were studied in vitro and in vivo to establish the significance of VEGF/VEGFR2 signaling.


RESULTS
Expression of VEGF and VEGFR2 was observed in 58% and 50% of urothelial tumor cells, respectively. VEGF expression failed to correlate with clinical variables. However, VEGFR2 expression correlated with disease stage (coefficient 0.23, p = 0.05). In addition, VEGFR2 expression increased with tumor invasion into the muscle (p <0.01). Experiments with VEGFR2 positive bladder cancer cell lines in vitro demonstrated increased invasion in response to VEGF. In addition, VEGF inhibition augmented the effect of docetaxel in a murine xenograft model of bladder cancer with a significant inhibition in proliferative index and microvascular density, and induction of apoptosis.


CONCLUSIONS
Increased VEGFR2 expression correlates with several features that predict progression of urothelial cancer, including disease stage and invasive phenotype. VEGF targeted therapy may enhance the efficacy of standard therapy for bladder cancer.
Xia
Guangbin
G
Department of Medicine, Keck School of Medicine of the University of Southern California, California, USA.
Kumar
S Ram
SR
Hawes
Debra
D
Cai
Jie
J
Hassanieh
Loubna
L
Groshen
Susan
S
Zhu
Sutao
S
Masood
Rizwan
R
Quinn
David I
DI
Broek
Daniel
D
Stein
John P
JP
Gill
Parkash S
PS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2