Cancer as an Embryological Phenomenon and Its Developmental Pathways: A Hypothesis regarding the Contribution of the Noncanonical Wnt Pathway

Figure 4

The embryonic model of cancer in the new context of adherens junctions. (a) E-cadherin as a functional platform that acts as both anchoring components of the canonical and noncanonical Wnt pathways and the Hippo signaling pathway and interacting with NF2/Merlin, Rho GTPases, and PAK-PIX-GIT. E-cadherin and α-catenin act as direct regulators of YAP1 and its homologue TAZ [66–68]. The canonical Hippo pathways [69], in vertebrate cells, act sequentially with MST1/2 and Lats1/2 [70, 71] to regulate the phosphorylation state of Yap1 (P, phosphate). Phosphorylation of YAP1 by Lat1/2 mediates sequestration of YAP1 in the cytoplasm while unphosphorylated YAP1 is translocated into the nucleus, where it drives the expression of genes that promote cell proliferation [71]. α-catenin depletion or deletion in keratinocytes shifts Yap1 into the nucleus and elevates nuclear Yap1 activity, thereby favoring cell proliferation. NF2/Merlin plays an inducer role (+) of the contact inhibition by the interaction with cadherins and catenins [72–76]. When activated, NF2/Merlin acts as a growth suppressor by inducing contact inhibition. An inducer signal is also obtained from CD44. There is evidence that Pak1 and Merlin interact reciprocally upon one other, such that Merlin also inhibits Pak1 function and suppresses the activation and the recruitment of Rac1 to the plasma membrane, which may be part of the mechanism by which Merlin regulates contact inhibition [73, 77–81]. Rho GTPases can be activated by growth factor-activated receptor or in response to cell-cell adhesion complex or cell-matrix adhesion receptors [82]. Rho GTPases participate in bidirectional signaling with both cadherins [83] and integrins [84]. In this initial context, Kaiso is found in the nucleus of the cell. (b) Kaiso in response to microenvironment signals is translocated to the cytoplasmic compartment. The immediate effect is to increase the expression of Wnt11 and Suz12 and the PCR2 complex would be involved in the repression of E-cadherin. Cytoplasmic Kaiso interacts with p120ctn and begins to destabilize the cell-cell adhesion complex. (c) The binding of Wnt to the Frizzled receptor leads to activation of Rho GTPases and PAK. p120ctn is a positive regulator of Rac1 [85] and thereby contributes to an alternative regulation of the recruitment of Rac1 to the cell-cell junctions. PAK represses NF2/Merlin and would contribute to destabilize the cell-cell adhesion complex, releasing Yap1, β-catenin, and the PAK-PIX-GIT complex. (d) YAP1, Pak1, and β-catenin, in the nucleus of the cell, activate proteins involved in processes such as cell proliferation and cell differentiation. DSH (Dishevelled); DAAM1 (Dishevelled Associated Activator of Morphogenesis 1); RAC, RhoA, and cdc42 (GTPases); p120ctn (p120 catenin); β-cat (β-catenin); α-cat (α-catenin); YAP1 (Yes-associated protein-1); PAK (p21-activated kinase); PIX (p21-activated kinase- (PAK-) interacting exchange factor); GIT (G-protein-coupled receptor-kinase-interacting protein); Lats1/2 (Large Tumor Suppressor 1 and 2, also known as Warts); Mst1/2 (Mammalian Sterile20-like 1 and 2); TK receptors (Tyrosine kinase receptors); CD44 (receptor for hyaluronic acid); Frizzled (family of G protein-coupled receptor proteins that serves as receptors in the Wnt signaling pathway).

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