Targeting Wnt Signaling in Endometrial Cancer

Abstract

This review presents new findings on Wnt signaling in endometrial carcinoma and implications for possible future treatments. The Wnt proteins are essential mediators in cell signaling during vertebrate embryo development. Recent biochemical and genetic studies have provided significant insight into Wnt signaling, in particular in cell cycle regulation, inflammation, and cancer. The role of Wnt signaling is well established in gastrointestinal and breast cancers, but its function in gynecologic cancers, especially in endometrial cancers, has not been well elucidated. Development of a subset of endometrial carcinomas has been attributed to activation of the APC/β-catenin signaling pathway (due to β-catenin mutations) and downregulation of Wnt antagonists by epigenetic silencing. The Wnt pathway also appears to be linked to estrogen and progesterone, and new findings implicate it in mTOR and Hedgehog signaling. Therapeutic interference of Wnt signaling remains a significant challenge. Herein, we discuss the Wnt-activating mechanisms in endometrial cancer and review the current advances and challenges in drug discovery.

Bone Marrow-Derived Cells in Endometrial Cancer Pathogenesis: Insights from Breast Cancer

“…However, in cancer, Wnt signaling is crucial in maintaining CSC stemness [ 62 ]. In EC specifically, the Wnt pathway is often dysregulated, characterized by increased mutations in β-catenin and expression of Wnt ligands within endometrial tissue [ 63 ]. Three Wnt ligands (WNT7A, WNT10A, and WNT10B) are significantly elevated in EC tumors in an estrogen-dependent manner, affecting primarily type-I EC [ 63 , 64 ].…”

“…In EC specifically, the Wnt pathway is often dysregulated, characterized by increased mutations in β-catenin and expression of Wnt ligands within endometrial tissue [ 63 ]. Three Wnt ligands (WNT7A, WNT10A, and WNT10B) are significantly elevated in EC tumors in an estrogen-dependent manner, affecting primarily type-I EC [ 63 , 64 ]. Wnt signaling, activated by the calcium binding protein, SPARC-related modular calcium binding 2 (SMOC-2), modulates stemness in eCSCs [ 65 ].…”

“…Although a multitude of pathways regulate CSC self-renewal and maintenance, a potential mechanism by which BMDCs may support ECCs is through the Wnt signaling pathway. As noted earlier, the Wnt pathway is often dysregulated in EC [ 63 ]. A question that remains to be elucidated is whether recruited BMDCs could be supporting ECCs in the primary site by modulating the Wnt pathway.…”

The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development

“…Given the current lack of therapeutic solutions for advanced and recurrent endometrial cancer, resent evidence support the role of Wnt signaling at early stages of endometrial tumorigenesis, The authors supported that Wnt signaling represents a promising intervention for targeted therapies in endometrial cancer patients. Various inhibitors targeting different molecules of this pathway have been developed including Medroxyprogesterone Acetate (MPA, Levonorgestrel Intrauterine Device, DKN-01 is a humanized monoclonal antibody (Mab) targeting Dickkopf-1 (DKK1), Porcupine Inhibitor, OMP-54F28 -a fusion protein consisting of the extracellular ligand-binding domain of Fzd8 and a human immunoglobulin G1 (IgG1) Fc domain-, Niclosamide, PRI-724 and ICG-001, Salinomycin, Curcumin and miRNA treatment, though only a few studies have addressed the effects of Wnt inhibitors in endometrial cancer and they are still at an early phase and far away from clinical trials [ 45 ].…”

“…Based on the outcomes of experiments, SYD985 recorded 10- to about 70-fold times more effective than TDM 1 and active against the USC unlike T-DM1.This demonstrates the heterogeneous HER2 expression. Concerning a trial (in phase I) for the HER2 expressing cancers, patients with endometrial carcinoma recorded a 39% response (phase II ongoing) [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”