Expression of thymidine phosphorylase and vascular endothelial growth factor in epithelial ovarian cancer: correlation with angiogenesis and progression of the tumor.
OBJECTIVE
The aim was first, to determine whether the expression of thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF) by epithelial ovarian cancer cells is correlated with the density of microvessels within the tumor and with ultrasonographic findings (B-mode classification and pulsed Doppler blood flow) and second, to speculate how these two angiogenesis factors participate in the tumorigenesis and tumor progression of epithelial ovarian cancer.


METHODS
B-mode ultrasonography and color Doppler imaging and pulsed Doppler spectral analysis were used to scan patients with an overt ovarian mass immediately before laparotomy. Sections of malignant tumors were analyzed for the cellular expression of TP and VEGF and the intratumoral density of microvessels by immunohistochemistry using antibodies to TP, VEGF and Factor VIII related antigen, respectively. The main outcome measures were the histological classification of the tumor, the stage of the disease, whether or not the tumor cells were TP and VEGF positive or negative, the microvessel count and B-mode classification and the peak systolic velocity (PSV).


RESULTS
Forty-four epithelial ovarian cancers were studied (6 of low malignant potential, 15 serous cystadenocarcinoma, 9 mucinous cystadenocarcinoma, 8 endometrioid adenocarcinoma, 4 clear cell carcinoma and 2 malignant Brenner tumor); 19 were Stage I, 6 Stage II, 15 Stage III and 4 Stage IV. Fourteen tumors (32%) were classified as TP positive and 21 (48%) as VEGF positive. The proportion of Stage I tumors that were TP positive (16%) was significantly lower (p = 0.022) than the corresponding value for Stages II-IV (44%), but the proportion with VEGF positive, the values for microvessel count and PSV were similar. Microvessel count did not significantly related to TP nor VEGF expression. The PSV was significantly higher in TP-positive tumors (p = 0.02) and VEGF-positive tumors (p = 0.006), respectively. There was a significant correlation between the microvessel count and the PSV (r = 0.34, p = 0.024). Moreover, specific B-mode classification significantly associated with disease stage and with TP expression, but not with VEGF expression.


CONCLUSIONS
Angiogenesis is an early, critical step in the tumorigenesis of epithelial ovarian cancer, however, it does not provide significant information about tumor aggressiveness. When TP expression is superimposed upon the VEGF expression, the tumor might acquire the aggressive tumor phenotype.
Department of Obstetrics and Gynecology, Shimane Medical University, Izumo 693-8501, Japan. hata31@shimane-med.ac.jp
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K
Hata
R
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Fujiwaki
K
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Nakayama
Y
Y
Maede
M
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Fukumoto
K
K
Miyazaki
D018262:Adenocarcinoma, Clear Cell / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D003536:Cystadenocarcinoma / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000032:analysis*; D005260:Female; D006801:Humans; D017078:Laser-Doppler Flowmetry; D008222:Lymphokines / Q000032:analysis*; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology*; D012044:Regression Analysis; D012189:Retrospective Studies; D013939:Thymidine Phosphorylase / Q000032:analysis*; D018615:Ultrasonography, Doppler, Color; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000032:analysis
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D013939:Thymidine Phosphorylase