Saeland Eirikur, van Vliet Sandra J, Bäckström Malin, van den Berg Venice C M, Geijtenbeek Teunis B H, Meijer Gerrit A, van Kooyk Yvette
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Cancer Immunol Immunother. 2007 Aug;56(8):1225-36. doi: 10.1007/s00262-006-0274-z. Epub 2006 Dec 29.
The epithelial mucin MUC1 is a high molecular weight membrane glycoprotein frequently overexpressed and aberrantly glycosylated in adenocarcinoma. Mucins normally contain high amounts of O-linked carbohydrate structures that may influence immune reactions to this antigen. During malignant transformation, certain glyco-epitopes of MUC1, such as Tn-antigen, TF-antigen and their sialylated forms become exposed. The role of these glycan structures in tumor biology is unknown, but their presence is known to correlate with poor prognosis in several adenocarcinomas. We analyzed the potency of MUC1 containing Tn-antigens (MUC1-Tn) to target C-type lectins that function as carbohydrate recognition and uptake molecules on dendritic cells (DC). We identified the macrophage galactose type C-type lectin (MGL), expressed by both DC and macrophages, as the receptor for recognition and binding of MUC1-Tn. To validate the occurrence of MGL-MUC1 interactions in situ, we studied the binding of MGL to MUC1 in primary colon carcinoma tissue. Isolation of MUC1 out of colon carcinoma tissue showed strong binding activity to MGL. Interestingly, MGL binding to MUC1 was highly correlated to binding by the lectin Helix pomatia agglutinin (HPA), which is associated with poor prognosis in colorectal cancer. The detection of MGL positive cells in situ at the tumor site together with the modified glycosylation status of MUC1 to target MGL on DC suggests that MGL positive antigen presenting cells may play a role in tumor progression.
上皮黏蛋白MUC1是一种高分子量膜糖蛋白，在腺癌中经常过度表达且糖基化异常。黏蛋白通常含有大量O-连接的碳水化合物结构，这些结构可能影响对该抗原的免疫反应。在恶性转化过程中，MUC1的某些糖表位，如Tn抗原、TF抗原及其唾液酸化形式会暴露出来。这些聚糖结构在肿瘤生物学中的作用尚不清楚，但已知它们的存在与几种腺癌的预后不良相关。我们分析了含有Tn抗原的MUC1（MUC1-Tn）靶向C型凝集素的能力，这些C型凝集素在树突状细胞（DC）上作为碳水化合物识别和摄取分子发挥作用。我们确定了由DC和巨噬细胞共同表达的巨噬细胞半乳糖型C型凝集素（MGL）作为识别和结合MUC1-Tn的受体。为了验证原位MGL-MUC1相互作用的发生，我们研究了MGL与原发性结肠癌组织中MUC1的结合。从结肠癌组织中分离出的MUC1显示出与MGL的强烈结合活性。有趣的是，MGL与MUC1的结合与凝集素蜗牛凝集素（HPA）的结合高度相关，HPA与结直肠癌的预后不良有关。在肿瘤部位原位检测到MGL阳性细胞以及MUC1的糖基化状态改变以靶向DC上的MGL，这表明MGL阳性抗原呈递细胞可能在肿瘤进展中起作用。
