Activation of macrophages by mucins produced from epithelial cancer cells and its effect

上皮癌细胞产生的粘蛋白对巨噬细胞的激活及其作用

• 批准号: 12672134
• 负责人: NAKADA Hiroshi
• 金额: $ 1.15万
• 依托单位: Kyoto Sangyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672134/
• 关键词: mucincyclooxyganase 2; macrophage; prostaglandin E2; cyclooxyganase 2; プロスタグランジンE_2; プロスタグランジンE2(PGE2); シクロオキシゲナーゼ2(COX-2); スカベンジャーリセプター

We found that mucins produced by epithelial cancer cells activated monocytes/macrophages. Monocytes incubated with mucins produced cytokines such as IL-1β and PGE2, which synthesis was elevated in a dose-dependent manner. Cyclooxygenase 2 (COX2) is a rate-limiting enzyme for biosynthesis of PGE2. It is noted that COX2 mRNA and enzyme protein were induced by mucins. We also examined immunohistochemically the localization of COX2 protein and mucins in human colorectal cancer tissues. It is noteworthy that COX2-expressing macrophages were located around the region in which mucins were detectable.Next, we examined the formation of cancer tissues using a mouse mammary tumor cell line, TA3-Ha and TA3-St. It is known that the former produces mucins named epiglycanin, but the latter does not. Although both cells grew at the similar rate in vitro, the former formed the cancer tissues much more rapidly than the latter in vivo. Induction of COX2 of infiltrated macrophages could be observed in the former tissues immunohistochemically but not in the latter. These results indicate that the induction of COX2 by mucins plays a significant role in the tumor formation.

我们发现上皮癌细胞产生的粘蛋白激活了单核细胞/巨噬细胞。与粘蛋白孵育的单核细胞产生细胞因子，如IL-1β和PGE2，其合成以剂量依赖性方式升高。环氧合酶2 （COX2）是生物合成PGE2的限速酶。我们注意到粘蛋白诱导了COX2 mRNA和酶蛋白的表达。我们也用免疫组织化学方法检测了COX2蛋白和粘蛋白在人类结直肠癌组织中的定位。值得注意的是，表达cox2的巨噬细胞位于可检测到粘蛋白的区域周围。接下来，我们使用小鼠乳腺肿瘤细胞系TA3-Ha和TA3-St检测癌组织的形成。众所周知，前者会产生一种叫做表胰甘肽的黏素，而后者则不会。尽管两种细胞在体外的生长速度相似，但前者在体内形成癌组织的速度要比后者快得多。免疫组化观察到前一种组织中浸润的巨噬细胞诱导COX2，后一种组织中没有。这些结果表明粘蛋白诱导COX2在肿瘤形成中起重要作用。

项目成果

H.Nakada: "Biosynthetic pathways of O-glycans in "Handbook of Glycosyl transferases and their Related Genes" (eds N.Taniguchi, K.Honke, M.Fukuda)"Springer-Verlag, Tokyo. 5 (2002)

H.Nakada：“《糖基转移酶及其相关基因手册》中的 O-聚糖生物合成途径（编辑 N.Taniguchi、K.Honke、M.Fukuda）”Springer-Verlag，东京。

K.Akita et al.: "Developmental expression of a unique carbohydrate antigen, Tn antigen, in mouse central nervous tissue"J.Neurosci.Res.. 65. 595-603 (2001)

K.Akita 等：“小鼠中枢神经组织中独特碳水化合物抗原 Tn 抗原的发育表达”J.Neurosci.Res.. 65. 595-603 (2001)

Guerre, S.V., Lo-Man, R., Bay, S., Deriaud, E., Nakada, H., Leclerc, C. and Cantacuzene, D.: "Short synthetic glycopeptides successfully induce antibody responses to carcinoma-associated Tn antigen"J. Peptide Res.. 55. 173-180 (2000)

Guerre, S.V.、Lo-Man, R.、Bay, S.、Deriaud, E.、Nakada, H.、Leclerc, C. 和 Cantacuzene, D.：“短合成糖肽成功诱导针对癌症相关 Tn 抗原的抗体反应

Inaba, T., Sano, H., Kawahito, Y., Hla, T., Akita, K., Toda, M., Yamashina, L., Inoue, M. and Nakada, H.: "Induction of cyclooxygenase-2 in monocyte/macrophage by inucins secreted from colon cancer cells"Proc. Natl. Acad. Sci. USA. 100. 2736-2741 (2003)

Inaba, T.、Sano, H.、Kawahito, Y.、Hla, T.、Akita, K.、Toda, M.、Yamashina, L.、Inoue, M. 和 Nakada, H.：“环氧合酶的诱导-

E.Osigana et al.: "Analysis of the fine specificity of Tn-binding proteins using synthetic glycopeptide epitopes and a biosensor based on surface plasmon resonance spectroscopy"FEBS Letters. 469. 24-28 (2000)

E.Osigana 等人：“使用合成糖肽表位和基于表面等离子体共振光谱的生物传感器分析 Tn 结合蛋白的精细特异性”FEBS Letters。