NGF-Enhanced Vasculogenic Properties of Epithelial Ovarian Cancer Cells Is Reduced by Inhibition of the COX-2/PGE2 Signaling Axis.

Maritza P Garrido,Alberto Selman,Manuel Valenzuela-Valderrama,Margarita Vega,Carmen Romero,Renato Salvatierra,Andrea Hernández,Iván Hurtado,Andrew F G Quest

doi:10.3390/cancers11121970

Abstract

Epithelial ovarian cancer (EOC) is a lethal gynecological neoplasia characterized by extensive angiogenesis and overexpression of nerve growth factor (NGF). Here, we investigated the mechanism by which NGF increases vascular endothelial growth factor (VEGF) expression and the vasculogenic potential of EOC cells, as well as the contribution of the cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) signaling axis to these events. EOC biopsies and ovarian cell lines were used to determine COX-2 and PGE2 levels, as well as those of the potentially pro-angiogenic proteins c-MYC (a member of the Myc transcription factors family), survivin, and β-catenin. We observed that COX-2 and survivin protein levels increased during EOC progression. In the EOC cell lines, NGF increased the COX-2 and PGE2 levels. In addition, NGF increased survivin, c-MYC, and VEGF protein levels, as well as the transcriptional activity of c-MYC and β-catenin/T-cell factor/lymphoid enhancer-binding factor (TCF-Lef) in a Tropomyosin receptor kinase A (TRKA)-dependent manner. Also, COX-2 inhibition prevented the NGF-induced increases in these proteins and reduced the angiogenic score of endothelial cells stimulated with conditioned media from EOC cells. In summary, we show here that the pro-angiogenic effect of NGF in EOC depends on the COX-2/PGE2 signaling axis. Thus, inhibition COX-2/PGE2 signaling will likely be beneficial in the treatment of EOC.

Highlights

Epithelial ovarian cancer (EOC) is the eighth largest cause of death by cancer in women worldwide [1,2]
Cells blocked the nerve growth factor (NGF)-induced increase in angiogenic score (Figure S9). These results demonstrate that the increase in vascular endothelial growth factor (VEGF) and the vasculogenic potential of EOC cells stimulated by NGF depends on activation of the COX-2/PGE2 signaling axis
In order to determine whether NGF effects on angiogenic proteins (c-MYC, survivin, and VEGF) depended on COX-2/PGE2 signaling, we evaluated the effects of a COX-2-specific inhibitor and direct stimulation with PGE2

Summary

Introduction

Epithelial ovarian cancer (EOC) is the eighth largest cause of death by cancer in women worldwide [1,2]. This pathology is characterized by non-specific symptoms and, is diagnosed at later stages, resulting in poor survival rates [3,4,5,6]. NGF represents both a direct and indirect angiogenic factor [9,11,12], as NGF increases VEGF levels in EOC cells [9,11] and binds to the high affinity receptor TRKA in endothelial cells, thereby increasing their proliferation, migration, and vasculogenesis [9,12]

Methods

Results

Conclusion