Abstract
Ovarian cancers represent the deadliest among gynecologic malignancies and are characterized by a hierarchical structure with cancer stem cells (CSCs) endowed with self-renewal and the capacity to differentiate. The Wnt/β-catenin signaling pathway, known to regulate stemness in a broad spectrum of stem cell niches including the ovary, is thought to play an important role in ovarian cancer. Importantly, Wnt activity was shown to correlate with grade, epithelial to mesenchymal transition, chemotherapy resistance, and poor prognosis in ovarian cancer. This review will discuss the current knowledge of the role of Wnt signaling in ovarian cancer stemness, epithelial to mesenchymal transition (EMT), and therapy resistance. In addition, the alleged role of exosomes in the paracrine activation of Wnt signaling and pre-metastatic niche formation will be reviewed. Finally, novel potential treatment options based on Wnt inhibition will be highlighted.
Highlights
Epithelial ovarian cancer (EOC) represents the deadliest among gynecologic malignancies [1]. This is mainly due to the fact that up to 80% of ovarian cancer patients present with symptoms and are subsequently diagnosed only at late disease stages, i.e., when metastases have already spread to pelvic organs, the abdomen, or beyond the peritoneal cavity [2]
Multiplegenetic alterations at a broad spectrum of oncogenes and tumor suppressor genes have been observed in ovarian cancer leading to deregulation of signal transduction pathways whose functions ranges from DNA repair, cell proliferation, apoptosis, cell adhesion, and motility
The LacZ+ ovarian surface epithelium (OSE) cells were enriched in SP positive cells, a sub-population of stem-like cells identified by their capacity to efflux the dye Hoechst 33342 by ATP-binding cassette super-family G member 2 (ABCG2) transporter pumps [34], a clinically relevant feature acquired by chemotherapy resistant ovarian cancer stem cells (CSCs)
Summary
Epithelial ovarian cancer (EOC) represents the deadliest among gynecologic malignancies [1]. Multiple (epi)genetic alterations at a broad spectrum of oncogenes and tumor suppressor genes have been observed in ovarian cancer leading to deregulation of signal transduction pathways whose functions ranges from DNA repair, cell proliferation, apoptosis, cell adhesion, and motility. The Wnt/β-catenin signaling pathway, known to regulate stemness in a broad spectrum of stem cell niches including the ovary, is thought to play an important role in ovarian cancer. The LacZ+ OSE cells were enriched in SP (side population) positive cells, a sub-population of stem-like cells identified by their capacity to efflux the dye Hoechst 33342 by ATP-binding cassette super-family G member 2 (ABCG2) transporter pumps [34], a clinically relevant feature acquired by chemotherapy resistant ovarian CSCs. Apart from its role during embryonic development of the ovary, Wnt signaling was shown to be an essential regulator of ovarian homeostasis, fertility, and tumorigenesis. The central role played by Wnt in regulating the delicate balance between stemness, proliferation, and differentiation to ensure ovarian tissue homeostasis is reflected by its causal association with ovarian cancer onset and/or progression as discussed
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