PMC

The canonical Wnt/β-catenin signaling pathway. Left panel: in the absence of Wnt ligand, β-catenin is sequestered by a protein complex composed of dishevelled (Dvl), adenomatous polyposis coli (APC), Axin1/2, Wilms tumor gene on X chromosome protein (WTX) and two kinases responsible for the phosphorylation of β-catenin, CK1α (casein kinase 1 alpha) and GSK3β (glycogen synthase kinase 3 beta). Then, YAP/TAZ (yes-associated protein/transcriptional co-Activator with a PDZ-binding domain) proteins recruit β-TrCP (beta-transducin-repeat-containing protein), a ubiquitin ligase responsible for the ubiquitination of β-catenin and its degradation by the proteasome pathway. In the nucleus, the transcriptional proteins of the TCF/LEF family (T-cell factor/lymphoid enhancer-binding factor) interact with the transcriptional repressors groucho/TLE (transducin-like cnhancer of split), recruiting histone deacetylases (HDACs) responsible for repressing transcription. Right panel: Binding of the Wnt ligands to the frizzled (Fzd) receptor and low-density-lipoprotein-related protein 5/6 (LRP5/6) co-receptor complex induces the recruitment of the scaffold protein Dvl to Fzd and leads to LRP5/6 phosphorylation (P) by CK1α and GSK3β kinases. The β-catenin destruction complex is then trapped to the membrane through Axin/Fzd interaction, leading to its inactivation. In parallel, Axin proteins are degraded following poly-ADP-ribosylation by tankyrases (TNKS). Newly synthesized β-catenin accumulates in the cytoplasm and translocates into the nucleus where it interacts with the transcription factors of the TCF/LEF family and with histones modifying co-activators p300 or CREB binding protein (CBP), B cell CLL/lymphoma 9 (BCL-9), brahma-related gene 1 (BRG1), and pygopus. These transcription complexes activate the transcription of target genes such as cMYC, AXIN2, BIRC5 or CCND1.

The crucial role of Wnt/β-catenin signaling pathway in multiple steps of bone sarcoma progression and metastatic dissemination. (a) The canonical Wnt/β-catenin signaling pathway is able to enhance bone sarcoma cells proliferation, to induce an epithelial-mesenchymal transition (EMT)-like through secretion of fibulin-3 and to promote the acquisition of stem cells properties of bone sarcoma cancer stem cells (CSCs). (b) The Wnt/β-catenin pathway participates to the hijacking of the bone microenvironment by the bone sarcoma cells, leading to the establishment of a vicious cycle between bone remodeling and tumor cells proliferation associated with the release of pro-tumoral factors including Wnt ligands from the bone matrix. (c) The Wnt/β-catenin pathway promotes the modulation of the extracellular matrix (ECM), increasing secretion of extracellular matrix components such as tenascin C, fibronectin 1 or collagens and stimulates the ECM degradation by upregulation of proteolytic enzymes such as MMPs. (d) The Wnt/β-catenin pathway induces an over-expression of vascular endothelial growth factor (VEGF), the most important pro-angiogenic factor and is also able to modulate endothelial cell migration, leading to an increase in tumor-associated angiogenesis. (e) The Wnt/β-catenin signaling pathway participates to the establishment of an immune tolerance in the TME, enhancing pro-tumoral M2 macrophages polarization and inhibiting cytotoxic T cell infiltration and functions and inducing resistance to anti-PD1 or anti-PDL-1 therapy. The activation of the Wnt/β-catenin signaling pathway in dendritic cells leads to up-regulation of interleukin-10 (IL-10) and indoleamine 2,3-dioxygenase 1 (IDO) secretion leading to an inhibition of tumor-infiltrating lymphocytes (TILs) cytotoxic properties. By targeting both osteosarcoma and Ewing sarcoma cells and the bone TME, the Wnt/β-catenin signaling pathway participates to the disease progression and the establishment of lung metastases.