Abstract

The activation of Wnt/-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/-catenin activity in gastric tumorigenesis. We found -catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc⁷¹⁶ mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-. Furthermore, treatment with TNF- induced glycogen synthase kinase 3 (GSK3) phosphorylation, which resulted in the stabilization of -catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear -catenin accumulation. These results suggest that macrophage-derived TNF- promotes Wnt/-catenin signalling through inhibition of GSK3, which may contribute to tumour development in the gastric mucosa.

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