Sugihara Ippei, Yoshida Masanobu, Shigenobu Tatsuro, Takagi Hiroaki, Maruyama Koji, Takeuchi Noriko, Toda Munetoyo, Inoue Mizue, Nakada Hiroshi
Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kyoto, Japan.
Cancer Res. 2006 Jun 15;66(12):6175-82. doi: 10.1158/0008-5472.CAN-05-3663.
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-gamma-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.
此前，我们发现MUC2粘蛋白可通过清道夫受体激活单核细胞/巨噬细胞，从而导致环氧化酶（COX）2的诱导及前列腺素E2（PGE2）的过量产生。为研究粘蛋白在荷瘤状态下的作用，我们比较了小鼠乳腺腺癌的产粘蛋白（TA3-Ha）和不产粘蛋白（TA3-St）克隆变体的皮下肿瘤形成情况。用表膜糖蛋白刺激腹膜巨噬细胞后，COX2 mRNA和蛋白的表达以及PGE2的产生均升高，表膜糖蛋白是TA3-Ha细胞产生的一种粘蛋白样糖蛋白。包含TA3-Ha细胞的皮下肿瘤组织比包含TA3-St细胞的组织生长快得多。与TA3-St肿瘤组织相比，TA3-Ha肿瘤组织中的COX2蛋白和血管内皮生长因子升高。尽管在两种肿瘤组织中通过免疫化学观察到的巨噬细胞数量相似，但COX2在TA3-Ha肿瘤组织浸润的巨噬细胞中显著诱导，而在TA3-St肿瘤组织中仅微弱诱导。此外，TA3-Ha肿瘤组织中的血管生成明显进展，而TA3-St肿瘤组织中仅轻微进展。表膜糖蛋白诱导的PGE2过量产生下调了巨噬细胞白细胞介素-12的产生。与荷TA3-St肿瘤小鼠相比，荷TA3-Ha肿瘤小鼠脾脏中产生干扰素-γ的CD4 T细胞显著减少，这表明粘蛋白导致PGE2介导的免疫抑制。实际上，口服COX2抑制剂可有效抑制TA3-Ha细胞异种移植物的肿瘤生长，但对TA3-St细胞异种移植物则无效。这些结果表明，粘蛋白通过过量产生PGE2在肿瘤进展中起重要作用。
