Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells

Abstract

The activation of Wnt/β‐catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/β‐catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β‐catenin activity in gastric tumorigenesis. We found β‐catenin nuclear accumulation in macrophage‐infiltrated dysplastic mucosa of the K19‐Wnt1 mouse stomach. Moreover, macrophage depletion in Apc Δ 716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β‐catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β‐catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)‐α. Furthermore, treatment with TNF‐α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β‐catenin. We also found that Helicobacter infection in the K19‐Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β‐catenin accumulation. These results suggest that macrophage‐derived TNF‐α promotes Wnt/β‐catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa.