Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance.
OBJECTIVE
The identification of novel molecular biomarkers, predicting outcome of ovarian cancer, is highly desirable. Considering that angiogenesis is a critical factor for ascites development and peritoneal dissemination in ovarian cancer and given that the vascular endothelial growth factor (VEGF) receptor signaling axis is a major driver of angiogenesis, we sought to analyze expression and compartmental distribution of VEGF-receptor family in ovarian cancer and to assess its clinical relevance with regard to established clinicopathological parameters, tumor cell dissemination to the bone marrow (BM) and the patient's survival.


METHODS
A total of 73 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGF-R1, VEGF-R2 and VEGF-R3 by immunohistochemistry. The presence of disseminated tumor cells (DTC) in the BM was analyzed by immunocytochemistry using the pancytokeratin antibody A45B/B3 and subsequent automatic detection based on staining and cytomorphology.


RESULTS
In primary ovarian cancer tissue, VEGF-receptor expression, detected with an overall frequency of 44%, was mostly located in the vascular wall and across the stroma; positivity rates for VEGF-R1, VEGF-R2 and VEGF-R3 were 34%, 18% and 26%, respectively. Total VEGF-receptor expression correlated with residual tumor after primary debulking surgery and the presence of DTC at primary diagnosis (p=0.035, p=0.023, respectively). Interestingly, VEGF-R1 positivity significantly correlated with decreased progression-free survival (p=0.026).


CONCLUSIONS
This is the first report, suggesting total VEGF-receptor status as a molecular biomarker for monitoring tumor cell spread to the BM and, particularly, revealing prognostic significance of VEGF-R1.
Department of Gynecology and Obstetrics, University Hospital of Essen, Germany; Department of Gynecology and Obstetrics, Technische Universität Dresden, Germany.
Pauline
P
Wimberger
Department of Gynecology and Obstetrics, University Hospital of Essen, Germany.
Issam
I
Chebouti
Department of Gynecology and Obstetrics, University Hospital of Essen, Germany.
Sabine
S
Kasimir-Bauer
Department of Gynecology and Obstetrics, Technische Universität Dresden, Germany.
Robert
R
Lachmann
Department for Medical Informatics and Biometry, Technische Universität Dresden, Germany.
Eberhard
E
Kuhlisch
Department of Gynecology and Obstetrics, University Hospital of Essen, Germany.
Rainer
R
Kimmig
Department of Anatomy and Cell Biology, University of Wuerzburg, Germany.
Ergün
E
Süleyman
Department of Gynecology and Obstetrics, University Hospital of Essen, Germany; Department of Gynecology and Obstetrics, Technische Universität Dresden, Germany. Electronic address: jan.kuhlmann@uniklinikum-dresden.de.
Jan Dominik
JD
Kuhlmann
D002288:Adenocarcinoma, Mucinous / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000556:secondary; D018284:Cystadenocarcinoma, Serous / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D018365:Neoplasm, Residual; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D055815:Young Adult
C501162:FLT1 protein, human; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
Angiogenesis; Bevacizumab; Disseminated tumor cells; Ovarian cancer; Vascular endothelial growth factor receptor