Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics

Abstract

Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial-mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications.

Keywords: Wnt inhibitors; Wnt signalling; cancer stem cells; cancer therapy; cancer-associated adipocytes; cancer-associated fibroblasts; tumour microenvironment; tumour vasculature; tumour-activated macrophages; tumour-infiltrating lymphocytes.

Figure 1

Wnt signalling—Canonical pathway in the ON and OFF state. When the frizzled family of receptors binds to the Wnt ligand, it recruits the dishevelled (Dsh) protein in the cell to frizzled receptors. Based on the dependency on β-catenin, the Wnt ligands are known to activate three different pathways—the canonical (β-catenin dependent) pathway, the noncanonical (β-catenin independent) pathway, and the noncanonical planar cell polarity pathway. In the ON state, the recruitment of Dsh to the cell membrane causes the disintegration of the APC degradation complex and the release of β-catenin. The free β-catenin can now translocate to the nucleus and bind to the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family to activate the transcription of target genes. In the OFF state, the destruction complex phosphorylates and ubiquitinizes the β-catenin, preventing the translocation and activation of β-catenin target genes inside the nucleus. The figure was made in Microsoft Office PowerPoint.

Figure 2

Different types of noncanonical Wnt signalling pathways. Activation of the planar cell polarity (PCP) pathway again depends on the association of (Fzd) protein with Dsh. The activated Fzd receptor recruits Dsh, which is associated with the dishevelled-associated activator of morphogenesis 1 (DAAM1), to activate the small G-protein Rho. Signalling downstream of Rho subsequently results in the modulation of the cytoskeleton. Dsh can also form a complex with Ras-related C3 botulinum toxin substrate 1 (Rac1), which regulates actin polymerisation. In addition, noncanonical Wnt signalling is also shown to use calcium as a secondary messenger to control cell fate. The presence of co-receptors in the proximity of Fzd receptors has been shown to influence the decision between canonical versus noncanonical Wnt signalling. The Wnt/Ca²⁺ pathway activates when the ligand binds the Fzd receptor and RYK/ROR co-receptors. This interaction increases the intracellular calcium levels and generates inositol 1,4,5-triphosphate-3 (IP3). The increased Ca²⁺ levels switch on the Ca²⁺ dependent calmodulin protein kinase (CaMKII), calcineurin, and protein kinase C (PKC). As a result, CAMKII and PKC phosphorylate the nuclear factor of activated T-cells (NFAT) and activate the transcription of target genes. The figure was made in Microsoft Office PowerPoint.

Figure 3

Tumour microenvironment in a healthy state vs. diseased state. The normal stromal cells are essential for maintaining the integrity of the neighbouring epithelial cells, and sustained cross-talk is observed for tissue homeostasis. Any aberrations in the normal stroma or the adjacent epithelial cells will significantly affect the stability of the tissues, which leads to tumorigenesis. The figure was made in Microsoft Office PowerPoint.

Figure 4

Wnt signalling orchestrates diverse interactions within the tumour microenvironment (TME). It drives the conversion of normal fibroblasts into cancer-associated fibroblasts (CAFs), stimulates tumour angiogenesis by endothelial cells (ECs), sustains stemness and self-renewal in cancer stem cells (CSCs), guides neuroendocrine and fat cell differentiation, and accelerates tumour progression, invasion, and metastasis. Moreover, Wnt signalling facilitates immune evasion by activating tumour-associated macrophages (TAMs), regulatory T-cells (Tregs), and tumour-infiltrating lymphocytes (TILs). The figure was made in Microsoft Office PowerPoint.

Figure 5

Modifications are brought about within the TME by various inhibitors targeting Wnt signalling, which can impede the tumour’s growth, invasion, and metastasis. These inhibitors have resulted in alterations of the different components of the TME, including cancer stem cells, endothelial cells, adipocytes, tumour-associated macrophages, and cancer-associated fibroblasts. The figure was made in Microsoft Office PowerPoint.