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Review
. 2019 Dec 16;10:2872.
doi: 10.3389/fimmu.2019.02872. eCollection 2019.

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

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Free PMC article
Review

Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights

Sonal Patel et al. Front Immunol. .
Free PMC article

Abstract

Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.

Keywords: anti-tumor response; immune response; immunotherapy; signaling; β-catenin.

Figures

Figure 1
Figure 1
Canonical Wnt signaling. In the absence of a Wnt ligand (left), the phosphorylation of β-catenin by destruction complex (composed of axin, APC, CK1, and GSK3β) leads to its ubiquitination by β-TrCP targeting it for proteasomal degradation. The absence of β-catenin in the nucleus results in the binding of the repressor complex containing TCF/LEF and TLE/Grouche to the target gene and thereby repressing its activity. Once the Wnt ligand binds to the Frizzled receptor and LRP co-receptor (right), LRP receptors are phosphorylated by CK1 and GSK3β, resulting in the recruitment of Dvl proteins to the plasma membrane where they activate and scaffold the β-catenin destruction complex. This results in the accumulation of β-catenin in the cytoplasm and its translocation to the nucleus where it forms a complex with TCF/LEF and transcribes target genes.
Figure 2
Figure 2
Non canonical Wnt signaling. In Wnt/PCP signaling (left), the binding of Wnt ligands to ROR-Frizzled receptor complex results in the activation of Dvl. The activated Dvl triggers the activation of small GTPase Rho by the de-inhibition of cytoplasmic protein DAAM. Rac1 and Rho together trigger ROCK and JNK and promote polarized cell migration. On the other hand, the WNT/Ca+2 pathway (right) activates PLC to produce DAG and IP3, leading to intracellular calcium fluxes that activate PKC isoforms other than calcineurin and calcium-modulated kinases (CAMKII), which then exhibit an NFAT-dependent transcriptional response.
Figure 3
Figure 3
Tumor immunomodulation by Wnt/β-catenin signaling. Wnt signaling induces elevated levels of intracellular β-catenin in malignant cells. This leads to the subsistence of Tregs, differentiation of CD4+ T cells to Th17 subtype, and secretion of IL10 and IL12 by DCs and dampened effector differentiation.
Figure 4
Figure 4
Targeting Wnt signaling to combat cancer. The Wnt pathway has multiple players that can be effectively targeted to modulate the signaling cascade, thereby inhibiting cancer proliferation. The targets that are showing promising results are highlighted in the figure. Several therapeutic molecules, such as anti-Frizzled antibodies, mimetics of Wnt molecules, disheveled inhibitors, tankyrase inhibitors, axin stabilizers, and inhibitors of TCF/CBP interactions are being evaluated in different phases of clinical studies.

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References

    1. Casey SC, Vaccari M, Al-Mulla F, Al-Temaimi R, Amedei A, Barcellos-Hoff MH, et al. . The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis. (2015) 36:S160–83. 10.1093/carcin/bgv035 - DOI - PMC - PubMed
    1. Gattinoni L, Ji Y, Restifo NP. Wnt/β- catenin signaling in T-cell immunity and cancer immunotherapy. Clin Cancer Res. (2010) 16:4695–701. 10.1158/1078-0432.CCR-10-0356 - DOI - PMC - PubMed
    1. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. (2017) 36:1461–73. 10.1038/onc.2016.304 - DOI - PMC - PubMed
    1. de Sousa E, Melo F, Vermeulen L. Wnt signaling in cancer stem cell biology. Cancers. (2016) 8:E60 10.3390/cancers8070060 - DOI - PMC - PubMed
    1. Suryawanshi A, Tadagavadi RK, Swafford D, Manicassamy S. Modulation of inflammatory responses by Wnt/β-catenin signaling in dendritic cells: a novel immunotherapy target for autoimmunity and cancer. Front Immunol. (2016) 7:460. 10.3389/fimmu.2016.00460 - DOI - PMC - PubMed

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