Wnt Signaling in Cell Motility and Invasion: Drawing Parallels between Development and Cancer

Abstract

The importance of canonical and non-canonical Wnt signal transduction cascades in embryonic development and tissue homeostasis is well recognized. The aberrant activation of these pathways in the adult leads to abnormal cellular behaviors, and tumor progression is frequently a consequence. Here we discuss recent findings and analogies between Wnt signaling in developmental processes and tumor progression, with a particular focus on cell motility and matrix invasion and highlight the roles of the ARF (ADP-Ribosylation Factor) and Rho-family small GTP-binding proteins. Wnt-regulated signal transduction from cell surface receptors, signaling endosomes and/or extracellular vesicles has the potential to profoundly influence cell movement, matrix degradation and paracrine signaling in both development and disease.

Keywords: Wnts; cancer; cell invasion; cell motility; development; small GTP-binding proteins.

Figure 1

Canonical and non-canonical Wnt pathways influence cell migration and invasion. Wnt activation may prompt the activation of multiple downstream signaling pathways, selected examples of which are shown here. Canonical Wnt signal transduction results in the dissociation of the “destruction complex” and stabilization of cytoplasmic β-catenin, which then translocates to the nucleus to regulate the transcription of downstream targets. Canonical Wnt signaling has also been shown to stimulate ARF6 activity, which in turn promotes the internalization of transcriptionally active β-catenin from sites of cadherin-based adhesion. Non-canonical signaling cascades promote the activation of the small GTPases Rac1, RhoA, and Cdc42 to promote the cytoskeletal remodeling needed for cell invasion and migration, as well as JNK to regulate additional transcriptional targets.

Figure 2

Wnt signaling impacts tumor progression and invasion. Wnt-regulated cellular changes include facilitating the dissociation and internalization of cadherin-based adhesions (cuboidal cells on the left) and the formation of invadopodia in migratory tumor cells (red). Wnt may also be included as cargo in extracellular vesicles released from amoeboid tumor cells (orange) as well as other cells such as fibroblasts in the tumor microenvironment (yellow). Small GTP-binding proteins of the ARF and Rho families, regulated by various GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs), mediate many of these processes.