WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Abstract

WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.

Long non-coding RNA HAGLR inhibits growth and metastasis and reduces stemness of lung cancer cells through the microRNA-330-3p/SLC34A2 axis

“…Since HAGLR could promote SCL24A2 expression, and SCL24A2 has been found to negatively regulate the Wnt/β-catenin pathway in NSCLC cells [33]. The Wnt/β-catenin signaling is implicated in multiple physiological processes including cell migration, polarization, as well as in maintenance and proliferation of cancer stem cells in the tumor bulk [34]. These findings suggested that activation of Wnt/β-catenin might be responsible for the growth and metastasis of LC cells.…”

CDK5RAP3 as a Novel Biomarker Signature Predicting Survival and Adjuvant Chemotherapeutic Benefit in Gastric Cancer

“…[28][29][30][31] Wnt/β-catenin signalling is essential for both tumour progression and the anti-tumour immune system. 9,20 The activation of β-catenin inhibits the transcription of chemokines C-C motif chemokine ligand 4 (CCL4) and reduces the recruitment and activation of basic leucine zipper ATF-like transcription factor 3 (BATF3)-lineage dendritic cells (DC) in the tumour microenvironment, thereby reducing the level of DC-derived C-X-C motif chemokine ligand 10 (CXCL10) and ultimately affecting the recruitment of T cells into the TME. 11,32 The Wnt/β-catenin signal activates T cell factor 1 (TCF-1) and blocks the transcriptional activity of forkhead box P3 (FoxP3) to affect the in ltration of regulatory T cells (Treg) into TME and dampen immunosuppressive activity of Treg cells.…”

“…Wnt/β-catenin signalling is associated with mechanistic development of immunity evasion, 20 and we previously showed that CDK5RAP3 negatively regulates the Wnt/β-catenin signalling pathway. We rst explored the responsiveness of patients to chemotherapy after inclusion of TIL.…”

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

“…On the other hand, extrinsic resistance occurs external to tumor cells through changes in T-cell activation. This involves regulatory T-cells (Tregs) [ 28 ], myeloid derived suppressor cells (MDSCs) [ 29 ], tumor-associated macrophages (TAMs) [ 30 ] and multiple canonical pathways [ 31 ] affecting the percentage of tumor infiltrating lymphocytes (TILs) and influencing the cytokine profile and cell toxicity [ 32 ].…”