Wnt5a Signaling in Gastric Cancer

Abstract

Gastric cancer remains an important health challenge, accounting for a significant number of cancer-related deaths worldwide. Therefore, a deeper understanding of the molecular mechanisms involved in gastric cancer establishment and progression is highly desirable. The Wnt pathway plays a fundamental role in development, homeostasis, and disease, and abnormal Wnt signaling is commonly observed in several cancer types. Wnt5a, a ligand that activates the non-canonical branch of the Wnt pathway, can play a role as a tumor suppressor or by promoting cancer cell invasion and migration, although the molecular mechanisms explaining these roles have not been fully elucidated. Wnt5a is increased in gastric cancer samples; however, most gastric cancer cell lines seem to exhibit little expression of this ligand, thus raising the question about the source of this ligand in vivo. This review summarizes available research about Wnt5a expression and signaling in gastric cancer. In gastric cancer, Wnt5a promotes invasion and migration by modulating integrin adhesion turnover. Disheveled, a scaffolding protein with crucial roles in Wnt signaling, mediates the adhesion-related effects of Wnt5a in gastric cancer cells, and several studies provide growing support for a model whereby Disheveled-interacting proteins mediates Wnt5a signaling to modulate cytoskeleton dynamics. However, Wnt5a might induce other effects in gastric cancer cells, such as cell survival and induction of gene expression. On the other hand, the available evidence suggests that Wnt5a might be expressed by cells residing in the tumor microenvironment, where feedback mechanisms sustaining Wnt5a secretion and signaling might be established. This review analyzes the possible functions of Wnt5a in this pathological context and discusses potential links to mechanosensing and YAP/TAZ signaling.

Keywords: Disheveled; Wnt5a; adhesion; gastric cancer; invasion; mechanosensing; metastasis.

FIGURE 1

Wnt5a signaling in gastric cancer (GC). Wnt5a interacts with APC and Daple to modulate integrin adhesion complex (IAC) turnover (1); this effect involves microtubule (MT) stabilization (2) and actin reorganization (3). Disheveled (Dvl) plays a central role in this signaling axis. In addition, other signals, such as CXCL16, can cooperate with Wnt5a. Wnt5a also correlates with increased expression of pro-inflammatory cytokines (4). Wnt5a might also induce changes in gene expression (5). For instance, LAMC2 is induced by Wnt5a, but other target genes might be also modulated. Finally, other signaling pathways might cooperate with Wnt5a signaling. Considering the evidence summarized here, YAP/TAZ signaling likely interacts with Wnt5a. This interaction might include direct modulation of actin remodeling (6a), as well as direct induction of WNT5A expression after YAP dephosphorylation (6b). Please note that Wnt5a might activate only some of these routes during specific stages along GC cell transformation. In addition, Dvl might be involved in all the signaling routes induced by Wnt5a. Physical interactions between Dvl and other proteins are indicated with blue arrows; biological effects are indicated by red lines. PM, plasma membrane. Frizzled-2 (Fzd2) and Ror2 are shown; however, other co-receptors and Frizzled members are likely involved. Some players and interactions are omitted for simplicity. See the main text for more details.

FIGURE 2

A general overview of Wnt5a signaling during GC. (1) Gastric epithelial cells might undergo epithelial-to-mesenchymal transition (EMT) in response to specific signals, such as loss of E-Cadherin expression (indicated as Mist1+ Cdh–/–). Transformed cells lose their epithelial characteristics, such as cell-cell interactions (dashed box). (2) Low levels of Wnt5a might be expressed by gastric epithelial cells. This source of Wnt5a might induce cell survival. (3) After the breakage of the basement membrane, transformed gastric cancer cells might find additional sources of Wnt5a, particularly from cancer-associated fibroblasts (CAFs) or tumor-associated macrophages (TAMs). In turn, increased levels of Wnt5a might signal through Frizzled (Fzd) receptors and co-receptors, such as Ror1/2 (Ror), to induce gene expression, integrin adhesion turnover, and other biological effects. (4) Integrins bind collagen in the tumor microenvironment (TME), forming integrin adhesion complexes (IACs). Increased turnover of IACs induced by Dvl-dependent Wnt5a signaling might promote migration and invasion of GC cells. In addition, the tumor microenvironment might provide mechanical cues, such as extracellular matrix stiffening. (5) Laminin γ2, which is expressed after Wnt5a stimulation, might also cooperate to promote enhanced invasiveness. Wnt5a can also induce the expression of pro-inflammatory molecules, leading to a sustained inflammatory environment, further stimulating Wnt5a secretion. Helicobacter pylori infection can also contribute to this environment, by promoting Wnt5a secretion.