The angiogenic "vascular endothelial growth factor/flk-1(KDR) receptor" pathway in patients with endometrial carcinoma: prognostic and therapeutic implications.
BACKGROUND
Vascular endothelial growth factor (VEGF) is an important endothelial cell mitogen associated with increased angiogenesis and aggressive tumor behavior. Its stimulating effect on endothelial cells basically is dependent on the presence of specific VEGF receptors, such as the flk-1(KDR) receptor. This study investigates the roles of VEGF and of a functionally intact angiogenic pathway, "VEGF/flk-1(KDR)," in patients with endometrial carcinoma and their significance in prognosis and therapy.


METHODS
A series of 121 endometrial carcinomas were studied. The expression of VEGF by endometrial tumor cells was assessed using the monoclonal antibody (MoAb) VG1. VEGF/KDR complexes on tumor endothelium or activated microvessel density (aMVD) were identified using the MoAb 11B5. In addition, the standard microvessel density (sMVD) was assessed with anti-CD31. In all tumors, the alkaline phosphatase/antialkaline phosphatase technique was employed. A Fisher exact test or an unpaired, two-tailed t test was used for testing correlations between categoric tumor variables, whereas a log-rank test was used to determine statistical differences between life tables. A Cox proportional hazards model was used to assess the effect of tumor variables on overall survival.


RESULTS
Cytoplasmic VEGF expression in > 50% of tumor cells was associated significantly with aMVD (P < 0.0001) and with sMVD (P < 0.003). In univariate survival analysis, VEGF (P = 0.0002), aMVD (P = 0.001), and sMVD (P = 0.0009) were significant prognostic variables. Equally important were the histologic parameters tumor type (P = 0.03), tumor grade (P = 0.003), and disease stage (P < 0.0001). In multivariate analysis, disease stage was the most important independent prognostic factor (P < 0.0001), followed by VEGF/KDR (P < 0.01), and VEGF (P < 0.04). Furthermore, VEGF and VEGF/KDR were the only independent prognostic variables for patients with Stage I endometrioid adenocarcinoma.


CONCLUSIONS
sMVD and the angiogenic factor VEGF are important indicators of a poor prognosis in patients with endometrial carcinoma. VEGF/KDR complexes define a subgroup of patients with endometrial carcinoma with an even worse prognosis.
Giatromanolaki
A
A
Department of Pathology, Democritus University of Thrace, Alexandroupolis, Greece. targ@her.forthnet.gr
Sivridis
E
E
Brekken
R
R
Thorpe
P E
PE
Anastasiadis
P
P
Gatter
K C
KC
Harris
A L
AL
Koukourakis
M I
MI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000473:pathology*; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis*; D008833:Microcirculation; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis*; D017978:Receptors, Growth Factor / Q000096:biosynthesis*; D040262:Receptors, Vascular Endothelial Growth Factor; D018570:Risk Assessment; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D014408:Biomarkers, Tumor; D016228:Endothelial Growth Factors; D008222:Lymphokines; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor