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

Y Nakanishi, M Nakatsuji, H Seno, S Ishizu… - …, 2011 - academic.oup.com
Y Nakanishi, M Nakatsuji, H Seno, S Ishizu, R Akitake-Kawano, K Kanda, T Ueo…
Carcinogenesis, 2011academic.oup.com
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 …
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.
Oxford University Press