Abstract POSTER-CTRL-1202: Suppression of cytokine expression and ovarian cancer invasion to omentum by vitamin D

Abstract

Abstract Purpose: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers, mainly because the disease, in most cases, has progressed to advanced stages when it is diagnosed. Our published studies have established a role for 1alpha,25-dihydroxyvitamin D3 (1,25D3) and its receptors (VDR) in suppressing ovarian tumor growth. The purpose of the present studies is to investigate the effect of the hormone and its receptors on OCa invasion. Approaches: Our microarray analyses have identified a group of cytokines of which the expression was suppressed by 1,25D3. Molecular analyses were used to define the mechanisms underlying the cytokine suppression. Trans-well assays were used to measure the in vitro effect of 1,25D3 on OCa invasion and migration. Ex vivo omental organ co-culturing with luciferase-marked human OCa cells was developed to investigate the effect of 1,25D3 and VDR on the ability of OCa cells to invade omentum. Syngeneic ovarian tumor models in VDR null mice were established to test the effect of stromal VDR in controlling OCa invasion in vivo. Data Summary: Mechanistic studies showed that the suppression of cytokine expression by 1,25D3 was mediated through NFκB inhibition. In trans-well assays, 1,25D3 treatment decreased the OCa motility and invasion through matrigel and VDR knockdown diminished such an effect. In ex vivo mouse models, the absence of the VDR in either the tumor cells or omentum resulted in increased invasiveness of OCa cells into omental tissues. In in vivo studies with syngeneic tumor models, mouse ovarian tumors invaded into omentum much more rapidly in VDR null than wild type mice, showing a role for stromal VDR in OCa invasion. Moreover, stable expression of constitutive IKKβ or the addition of recombinant cytokines in the culture medium relieved the suppressive effect of 1,25D3 on OCa migration and invasion, identifying the suppression of cytokine expression and NFκB activity as the main mechanism underlying the inhibitory effect of 1,25D3 on OCa invasion. Conclusions: This is the first demonstration of an important role of 1,25D3 in suppressing cytokine expression and ovarian tumor invasion into omentum. The studies are also the first to define a role for both tumor and stromal VDR in the suppression. The studies support a VDR-based therapeutic strategy that will allow the use of 1,25D3 or its analogs to improve the poor clinical outcomes for patients with invasive OCa. The main findings of the present study is that the VDR acts as a suppressor of ovarian tumor invasion and thus represents a novel molecular drug target for the intervention of invasive OCa. Citation Format: Lungchukiet Panida, Kasiappan Ravi, Sun Yuefeng, Quarni Waise, Santo Nicosia, Xiaohong Zhang, Wenlong Bai. Suppression of cytokine expression and ovarian cancer invasion to omentum by vitamin D [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-CTRL-1202.