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Different Progression of Tumor Xenografts between Mucin-Producing and Mucin–Non-Producing Mammary Adenocarcinoma-Bearing Mice

¹ Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kyoto, Japan and ² Core Research for Educational Science and Technology Project, Japan Science and Technology Agency, Saitama, Japan

Requests for reprints: Hiroshi Nakada, Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kita-ku, Kyoto 630-8555, Japan. Phone: 81-75-705-1897; Fax: 81-75-705-1888; E-mail: hnakada{at}cc.kyoto-su.ac.jp.

Previously, we found that MUC2 mucins could activate monocytes/macrophages through a scavenger receptor leading to cyclooxygenase (COX) 2 induction and overproduction of prostaglandin E₂ (PGE₂). To investigate the role of mucins in the tumor-bearing state, we compared s.c. tumor formation by using mucin-producing (TA3-Ha) and mucin–non-producing (TA3-St) cloned variants of mouse mammary adenocarcinomas. Expression of COX2 mRNA and protein and production of PGE₂ were elevated in peritoneal macrophages stimulated with epiglycanin, which is a mucin-like glycoprotein produced by TA3-Ha cells. S.c. tumor tissues comprising TA3-Ha cells grew much faster than tissues comprising TA3-St cells. COX2 protein and vascular endothelial growth factor in TA3-Ha tumor tissues were elevated compared with the TA3-St tumor tissues. Although similar numbers of macrophages were observed immunochemically in the two types of tumor tissues, COX2 was induced prominently in the infiltrating macrophages in TA3-Ha tumor tissues but only faintly in TA3-St tumor tissues. Furthermore, angiogenesis progressed remarkably in TA3-Ha tumor tissues but only slightly in TA3-St tumor tissues. Epiglycanin-induced overproduction of PGE₂ down-regulated interleukin-12 production by macrophages. IFN--producing CD4 T cells in spleens obtained from TA3-Ha tumor-bearing mice were significantly reduced compared with TA3-St tumor-bearing mice, suggesting that mucins cause PGE₂-mediated immune suppression. Actually, the tumor growth of a TA3-Ha cell xenograft was suppressed effectively by oral administration of a COX2 inhibitor but that of a TA3-St cell one was not. These results suggest that mucins play an important role in tumor progression through overproduction of PGE₂. (Cancer Res 2006; 66(12): 6175-82)