COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps

Abstract

Macrophages are a major component of tumor stroma. Tumor-associated macrophages (TAMs) show anti- (M1) or protumor (M2) functions depending on the cytokine milieu of the tumor microenvironment. Cyclooxygenase-2 (COX-2) is constitutively expressed in a variety of tumors including colorectal cancer. TAMs are known to be a major source of COX-2 in human and mice intestinal tumors. COX-2 inhibitor reduces the number and size of intestinal adenomas in familial adenomatous polyposis patients and Apc(Min/+) mice. Although COX-2 inhibitor is thought to regulate cancer-related inflammation, its effect on TAM phenotype remains unknown. Here, we examined the effects of COX-2 inhibition on TAM phenotype and cytokine expression both in vivo and in vitro. Firstly, the selective COX-2 inhibitor celecoxib changed the TAM phenotype from M2 to M1, in proportion to the reduction in number of Apc(Min/+) mouse polyps. Concomitantly, the expression of M1-related cytokine interfron (IFN)-γ was significantly upregulated by celecoxib, although the M2-related cytokines interleukin (IL)-4, IL-13 and IL-10 were not significantly altered. Secondly, IFN-γ treatment attenuated M2 phenotype of mouse peritoneal macrophages and oriented them to M1 even in the presence of M2-polarizing cytokines such as IL-4, IL-13 and IL-10. Thus, our results suggest that COX-2 inhibition alters TAM phenotype in an IFN-γ-dependent manner and subsequently may reduce intestinal tumor progression.

Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

“…Complementally, we determined that human soluble SEMA4D protein could mediate polarization of MOs toward M2-like phenotypes with characteristics of increasing CD163 expression, which was analogous to other literatures that confirmed several cytokines, associated with immune and inflammation response, alters the phenotype of tumor-associated macrophages from M2 to M1, including coagulation factor XII (FXII), COX-2 inhibition, IL-10 Wang et al, 2010;Nakanishi et al, 2011). Further validated work that SEM4D, as important player in immune and inflammation, induced macrophage polarization in tumor progression is needed in the future.…”

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

“…It has recently been shown that COX-2 is important for the M2-polarization of TAMs in Apc Min mouse tumors [92]. Accordingly, it is possible that the COX-2/PGE 2 pathway-induced inflammatory network is important for education of macrophages into the pro-tumorigenic M2 or M2-like types.…”

Targeting Inflammation to Improve Tumor Drug Delivery

“…In that regard, inhibition of COX-2 activity inhibits hypoxic cancer cell-induced M2-polarization of macrophages [59], and use of the selective COX-2 inhibitor celecoxib (Table 2) changes macrophage phenotype from M2 to M1 in a mouse model of colon cancer [60]. Moreover, similar effect was recently seen using the lipid mediator lipoxin LXA 4 , ( Table 1) [61].…”

“…Indeed, this macrophage shift from pro-tumor M2 phenotype to anti-tumor M1 phenotype has been proposed as a beneficial anti-cancer therapeutic target [57,58]. Importantly, there is evidence indicating that COX-2 is an important participant in macrophage polarization [59].In that regard, inhibition of COX-2 activity inhibits hypoxic cancer cell-induced M2-polarization of macrophages [59], and use of the selective COX-2 inhibitor celecoxib (Table 2) changes macrophage phenotype from M2 to M1 in a mouse model of colon cancer [60]. Moreover, similar effect was recently seen using the lipid mediator lipoxin LXA 4 , (Table 1) [61].…”