Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas

Abstract

Semaphorins (SEMAs) compete with vascular endothelial growth factor (VEGF) for receptor neuropilin 1 (NP1) and 2 (NP2) and suppress angiogenesis. To clarify the involvement of SEMA and VEGF in the development and progression of ovarian carcinoma, we analyzed the immunohistochemical expression of SEMA, VEGF, NP1, and NP2 in 105 epithelial ovarian tumors. In addition, loss of heterozygosity at SEMA gene loci was examined. Strong expression of SEMA was found in 48% of benign, 33% of borderline tumors, and 13% of carcinomas (P < .05). Positivity for SEMA was significantly decreased in stage IV carcinomas and the expression of SEMA was significantly lower in peritoneal metastases than in primary lesions. Expression of SEMA showed a weak inverse correlation with microvessel density, but the correlation was not statistically significant. Loss of heterozygosity at SEMA3B or SEMA3F was demonstrated in none of the benign tumors, 8% of borderline tumors, and 29% of carcinomas. Expression of NP1 and NP2 was significantly higher in carcinomas than in benign tumors (P < .0001 and .0002, respectively). Patients with ovarian carcinoma with a high VEGF/SEMA ratio showed poorer survival than those with a low VEGF/SEMA ratio (P = .005). Decreased expression of SEMA and increased expression of NP1 and NP2 are characteristics of ovarian carcinomas, and loss of SEMA expression may play an important role in ovarian carcinoma progression. A high VEGF/SEMA ratio has adverse prognostic significance in patients with ovarian carcinoma.