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

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.

Targeting IL-3Rα on tumor-derived endothelial cells blunts metastatic spread of triple-negative breast cancer via extracellular vesicle reprogramming

“…In this study, we have demonstrated that anti-IL-3R-EVs also reduce β-catenin expression in tumor-bearing mice, suggesting that anti-IL-3R-EVs are also able to target the canonical wingless Wnt/β-catenin pathway in neoplastic cells. β-catenin accumulation and the acquisition of mesenchymal markers, as Vimentin, in tumor cells, are associated with cancer cells’ ability to spread to distant sites 48 – 50 . Indeed, anti-IL-3R-EVs were found effective in reducing the expression of Vimentin, and animals treated with anti-IL-3R-EVs were almost protected from the occurrence of liver and lung metastasis.…”

Export Control: Post-transcriptional Regulation of the COPII Trafficking Pathway

“…A second example of trafficking control through cargo PTMs is provided by Sun et al (2017) in their study of Wnts ( Figure 5B ). Wnts are an important class of cell surface receptors that are required for embryonic development in animals and are dysregulated in human cancers ( Steinhart and Angers, 2018 ; Patel et al, 2019 ). Wnt secretion requires the transmembrane protein Wntless, which binds Wnts directly, but the mechanisms controlling Wnt/Wntless vesicle assembly and trafficking are incompletely understood.…”

Analysis of N6-methyladenosine (m6A) methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer

“…In addition, Wnt signaling also plays an important role in the regulation of tumor immune microenvironment, which can regulate the in ltration and activity of various types of T cells in tumors. Usually excessive activation of Wnt signaling pathway in tumors can lead to tumor immunosuppression and immune escape [49,50]. In colorectal cancer, inhibiting the activation of the Wnt signaling pathway can reduce the in ltration of Treg cells in the tumor and up-regulate the content of CD8 + T cells in the tumor, thereby enhancing the response to immunotherapy [51].…”