Multiple Targets of the Canonical WNT/β-Catenin Signaling in Cancers.

Yves Lecarpentier,Olivier Schussler,Alexandre Vallée,Jean-Louis Hébert

doi:10.3389/fonc.2019.01248

Abstract

Canonical WNT/β-catenin signaling is involved in most of the mechanisms that lead to the formation and development of cancer cells. It plays a central role in three cyclic processes, which are the cell division cycle, the immune cycle, and circadian rhythms. When the canonical WNT pathway is upregulated as in cancers, the increase in β-catenin in the nucleus leads to activation of the expression of numerous genes, in particular CYCLIN D1 and cMYC, where the former influences the G1 phase of the cell division cycle, and the latter, the S phase. Every stage of the immune cycle is disrupted by the canonical WNT signaling. In numerous cancers, the dysfunction of the canonical WNT pathway is accompanied by alterations of the circadian genes (CLOCK, BMAL1, PER). Induction of these cyclic phenomena leads to the genesis of thermodynamic mechanisms that operate far from equilibrium, and that have been called “dissipative structures.” Moreover, upregulation of the canonical WNT/β-catenin signaling is important in the myofibroblasts of the cancer stroma. Their differentiation is controlled by the canonical WNT /TGF-β1 signaling. Myofibroblasts present ultraslow contractile properties due to the presence of the non-muscle myosin IIA. Myofibroblats also play a role in the inflammatory processes, often found in cancers and fibrosis processes. Finally, upregulated canonical WNT deviates mitochondrial oxidative phosphorylation toward the Warburg glycolysis metabolism, which is characteristic of cancers. Among all these cancer-generating mechanisms, the upregulated canonical WNT pathway would appear to offer the best hope as a therapeutic target, particularly in the field of immunotherapy.

Highlights

Since the discovery in 1982 of Int1 (WNT1a) as an oncogene reported in murine breast cancers, the canonical WNT/β-catenin pathway has often been found to be associated with cancer [1]
It has been reported that three major cyclic processes namely the cell division cycle [2,3,4], the immune cycle [5], and circadian rhythms (CRs) [6] become highly disturbed due to Canonical WNT/β-Catenin Signaling in Cancers upregulation of the canonical WNT signaling
The canonical WNT signaling plays a central role in the cell division cycle, because the two nuclear β-catenin targets CYCLIN D1 and cMYC intervene at two key checkpoints of the cell cycle

Summary

Introduction

Since the discovery in 1982 of Int1 (WNT1a) as an oncogene reported in murine breast cancers, the canonical WNT/β-catenin pathway has often been found to be associated with cancer [1]. Aerobic glycolysis in tumor cells, which is partly responsible for shunting the mitochondrial oxidative phosphorylations [Warburg effect [15]], is related to the upregulation of the canonical WNT pathway. CANONICAL WNT/β-CATENIN SIGNALING, CELL DIVISION CYCLE AND CANCER The canonical WNT signaling plays a central role in the cell division cycle, because the two nuclear β-catenin targets CYCLIN D1 and cMYC intervene at two key checkpoints of the cell cycle.

Results

Conclusion