Wnt Signaling in Ovarian Cancer Stemness, EMT, and Therapy Resistance

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.

LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

“…Deregulations of the Wnt/β-catenin signaling pathway have been associated with the etiology of different human cancers, including colorectal, prostate, breast and skin cancers [85][86][87][88]. Accordingly, the Wnt/β-catenin signaling has been shown to play critical role in EOC development, including EOC stemness, EMT, progression to malignancy, and therapy resistance (recently reviewed in [89,90]). The β-catenin is the key mediator of this pathway, as in the presence of Wnt ligands, the Frizzled and LRP5/6 receptors prevent the formation of the destruction Axin/Apc2/Gskβ complex, allowing the stabilized β-catenin to translocate to the nucleus and to interact with the TCF/LEF transcription factors, thus modulating the transcription of Wnt downstream target genes, many of which regulate EMT, invasion, and metastasis [89].…”

Wnt Signaling in Gynecologic Malignancies

“…The epithelial to mesenchymal transition (EMT) is the process by which epithelial cells transform into a more motile, invasive mesenchymal phenotype. It conveys resistance to anoikis in cancer cells, thus promoting cancer cell migration and peritoneal metastasis in HGSOC [9]. Wnt/β-catenin signaling plays a crucial role in EMT and metastasis in many cancers, including ovarian [10,11].…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…As a physiological process, EMT is observed during organogenesis, tissue development, remodeling, and wound healing [52][53][54]; contrarily, any deregulations might induce carcinogenesis [55,56]. EMT-induced carcinogenesis is the prevalent cause of various malignancies including head and neck squamous cell carcinoma, papillary thyroid carcinoma, lung, pancreatic, gastric, ovarian, prostate, and breast cancer [57][58][59][60][61][62][63][64][65][66][67][68].…”