Abstract 958: Recruitment of tumor-associated macrophages by cooperation of PGE2 pathway and infectious stimulation

Abstract

Abstract Gastric cancer development is tightly associated with Helicobacter infection, which induces expression of COX-2 and mPGES-1 resulting in activation of PGE2 pathway in gastric mucosa. It has been established that PGE2 pathway plays a key role in chronic inflammation and tumorigenesis in the stomach. However, mechanisms of PGE2 or PGE2-induced inflammation underlying tumorigenesis have not been fully understood yet. On the other hand, tumor associated macrophages play an important role in tumorigenesis through expression of growth factors, induction of angiogenesis, remodeling and suppression of acquired immunity. We previously showed that macrophage infiltration was enhanced in K19-C2mE transgenic mouse stomach, in which PGE2 pathway is induced by expression of COX-2 and mPGES-1. Moreover, accumulated macrophages in gastric mucosa were activated, which was suppressed by treatment of the mice with antibiotics. These results suggested that both PGE2 pathway and infectious stimulation are important for macrophage infiltration and activation during tumorigenesis. To investigate the effect of PGE2 and infectious stimuli in gastric tumorigenesis, we generated germfree colony of K19-Wnt1/C2mE transgenic mice and examined gastric phenotypes. K19-Wnt1/C2mE mice develop dysplastic gastric tumors caused by simultaneous activation of Wnt signaling and PGE2 pathway. Importantly, germfree K19-Wnt1/C2mE mice showed significant suppression of gastric tumor development with decreased macrophage infiltration. Moreover, Helicobacter infection to germfree K19-Wnt1/C2mE mice induced gastric tumor development. These results indicate that infectious stimuli to gastric mucosa are required for tumor formation. We also found that PGE2 pathway together with bacterial infection induced expression of monocyte-attractant chemokine CCL2 in the gastric mucosa and macrophage cell line. Notably, infiltrated macrophages showed “alternatively” activated M2 properties, which are characteristics of tumor-associated macrophages. Finally, inhibition of COX-2/PGE2 pathway in K19-Wnt1/C2mE mice caused significant suppression of macrophage infiltration and gastric tumorigenesis. These results suggest that PGE2 signaling and bacterial infectious stimulation cooperatively recruit protumorigenic macrophages through induction of chemokines, and that recruitment of tumor-associated macrophages is one of the important mechanisms of PGE2 signaling in tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 958.