Clinical Impact of RANK Signalling in Ovarian Cancer.

Verena Wieser,Hubert Hackl,Susanne Sprung,Johannes Haybaeck,Alain Gustave Zeimet,Christian Marth,Irina Tsibulak,Heidelinde Fiegl

doi:10.3390/cancers11060791

Verena Wieser, Hubert Hackl + Show 6 more

Open Access

https://doi.org/10.3390/cancers11060791

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Journal: Cancers	Publication Date: Jun 8, 2019
Citations: 12	License type: CC BY 4.0

Affiliation: Innsbruck Medical University, Universität Innsbruck

Abstract

Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

Highlights

Ovarian cancer (OC) is one of the most common cancers amongst women in Europe and the leading cause of death in gynaecological cancers [1]
RANK ligand (RANKL) Is Highly Expressed in OC and BRCA1/2 Mutated Tumours
We found highly elevated RANKL and OPG expression in OC

Summary

Introduction

Ovarian cancer (OC) is one of the most common cancers amongst women in Europe and the leading cause of death in gynaecological cancers [1]. The interplay of receptor activator of nuclear factor-κB (RANK), its ligand RANKL and Osteoprotegerin (OPG) are established regulators of bone metabolism. RANKL expressed on osteoblasts activates RANK signalling and transcriptional activation of osteoclasts which promote. The endogenous OPG functions as a soluble decoy receptor preventing RANKL from activating its receptor RANK [4]. Previous studies demonstrated that RANKL mediates progesterone-driven mammary carcinogenesis [8,9,10] and RANK/RANKL signalling controlled BRCA1 mutation-driven mammary tumours [11]. Sigl et al demonstrated that the genetic and pharmacological inhibition of RANKL in mice abolished the occurrence of Brca mutation-driven pre-neoplastic lesions [11]. RANK/RANKL blockade impaired proliferation and expansion of mammary progenitors from human BRCA1 mutation carriers indicating a significant role of RANK/RANKL signalling in inherited BC. BC and OC present as distinct clinical entities, recent evidence supported a substantial overlap with respect to genetic and epigenetic alterations [12]

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