DEAD-Box Helicase 4 (Ddx4)+ Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers.

Stella D’Oronzo,Erica Silvestris,Paola Cafforio,Gennaro Cormio,Angelo Paradiso,Domenica Lovero,Raffaele Palmirotta,Franco Silvestris,Loren Duda

doi:10.3390/ijms21176096

Abstract

DEAD-Box Helicase 4 (Ddx4)+ ovarian stem cells are able to differentiate into several cell types under appropriate stimuli. Ddx4 expression has been correlated with poor prognosis of serous ovarian cancer (OC), while the potential role of Ddx4+ cells in non-serous epithelial OC (NS-EOC) is almost unexplored. The aim of this study was to demonstrate the presence of Ddx4+ cells in NS-EOC and investigate the effect of follicle-stimulating hormone (FSH) on this population. Increased Ddx4 expression was demonstrated in samples from patients with advanced NS-EOC, compared to those with early-stage disease. Under FSH stimulation, OC-derived Ddx4+ cells differentiated into mesenchymal-like (ML) cells, able to deregulate genes involved in cell migration, invasiveness, stemness and chemoresistance in A2780 OC cells. This effect was primarily induced by ML-cells deriving from advanced NS-EOC, suggesting that a tumor-conditioned germ cell niche inhabits its microenvironment and is able to modulate, in a paracrine manner, tumor cell behavior through transcriptome modulation.

Highlights

Ddx4 is a member of the DEAD box protein family physiologically involved in the gametogenesis, division and development of primordial germ cells, as well as cellular growth [1]
ovarian stem cells (OSCs) are spherical cells slightly larger than the very small embryonic-like stem cells (VSELs) [7], and their stemness is supported by the expression of typical markers as OCT4, NANOG, SSEA1 and SSEA4 [8] as well as by others shared by cancer stem cells, including CD44, LGR5, and CD133 molecules [8,9]
In relation to the reciprocal transdifferentiation with cells of mesenchymal lineage, Ddx4+ cells, as multipotent stem cells expressing major stemness markers [8], are usually considered ontogenetically incline to the mesodermal differentiation and efficient supporters of ovarian cancer (OC) growth, since they are largely expressed by high-grade serous cancers [3]

Summary

Introduction

Ddx is a member of the DEAD box protein family physiologically involved in the gametogenesis, division and development of primordial germ cells, as well as cellular growth [1]. OSCs are reported to home within the ovarian cortex even in post-menopausal women and are suspected to support neo-oogenesis and primordial follicle assembly in response to the follicle stimulating hormone (FSH) through its alternatively spliced receptor variant 3 (FSHR3) [10]. These cells have been demonstrated to differentiate in vitro to large oocyte-like cells resembling mature oocytes [11] and to be suitable to restore fertility in pharmacologically sterilized animal models [12]. OSCs are suspected to contribute to epithelial OC development in relation to their high sensitivity to FSH [13,14]

Objectives

Methods

Conclusion