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纤连蛋白糖基化的癌症相关变化。由单克隆抗体定义的癌胚纤连蛋白的免疫组织学定位。

Cancer-associated changes in glycosylation of fibronectin. Immunohistological localization of oncofetal fibronectin defined by monoclonal antibodies.

作者信息

Mandel U, Hamilton Therkildsen M, Reibel J, Sweeney B, Matsuura H, Hakomori S, Dabelsteen E, Clausen H

机构信息

Department of Oral Diagnostics, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Denmark.

出版信息

APMIS. 1992 Sep;100(9):817-26.

PMID:1389100
Abstract

The extracellular matrix adhesion molecule fibronectin exhibits different isoforms derived by alternative splicing as well as recently demonstrated variation in O-glycosylation. Although fibronectin is widely distributed in normal tissues, the individual isoforms have been found to show restricted tissue distribution and association with malignancies. The monoclonal antibody FDC-6 defines a cancer-associated de novo glycosylation of a specific threonine residue in the C-terminal region of the fibronectin molecule termed oncofetal fibronectin. Here we report an immunohistological study of oral squamous cell carcinomas (n = 33), premalignant lesions (n = 15), and normal oral mucosa (n = 10) using the FDC-6 antibody. A selective expression of the oncofetal fibronectin epitope was demonstrated in close relation to the invading carcinoma, whereas no staining was observed in premalignant lesions without epithelial dysplasia, or in normal epithelium. Furthermore, we attempted to identify additional carbohydrate-related epitopes distinguishing fibronectin of human hepatoma cell line HUH-7 from plasma fibronectin. No novel epitopes were identified, as all generated monoclonal antibodies lacking reactivity with plasma fibronectin showed the same specificity as FDC-6. Previous studies have indicated that the de novo glycosylation is induced by a novel transferase activity only found in fetal and carcinoma cell lines, placenta and hepatoma tissues. Here we provide further evidence that a purified UDP-GalNAc:peptide N-acetylgalactosaminyltransferase from normal bovine thymus and human placentae is incapable of utilizing the hexapeptide VTHPGY as a substrate. The results demonstrate that oncofetal fibronectin is highly associated with malignancy, and appears to be induced by expression of a unique glycosyltransferase or modification of the specificity of the normally expressed transferase.

摘要

细胞外基质黏附分子纤连蛋白通过可变剪接呈现出不同的异构体,并且最近还发现其O-糖基化存在差异。尽管纤连蛋白广泛分布于正常组织中,但已发现各个异构体显示出有限的组织分布以及与恶性肿瘤的关联。单克隆抗体FDC-6可识别纤连蛋白分子C端区域中特定苏氨酸残基的一种癌症相关的从头糖基化,这种糖基化产物被称为癌胚纤连蛋白。在此,我们报告了一项使用FDC-6抗体对33例口腔鳞状细胞癌、15例癌前病变和10例正常口腔黏膜进行的免疫组织学研究。结果表明,癌胚纤连蛋白表位的选择性表达与侵袭性癌密切相关,而在无上皮发育异常的癌前病变或正常上皮中未观察到染色。此外,我们试图鉴定出其他与碳水化合物相关的表位,以区分人肝癌细胞系HUH-7中的纤连蛋白与血浆纤连蛋白。未鉴定出新的表位,因为所有产生的与血浆纤连蛋白无反应性的单克隆抗体都显示出与FDC-6相同的特异性。先前的研究表明,这种从头糖基化是由仅在胎儿和癌细胞系、胎盘及肝癌组织中发现的一种新型转移酶活性所诱导的。在此,我们提供了进一步的证据,即从正常牛胸腺和人胎盘中纯化的UDP-GalNAc:肽N-乙酰半乳糖胺基转移酶无法将六肽VTHPGY作为底物。这些结果表明,癌胚纤连蛋白与恶性肿瘤高度相关,并且似乎是由一种独特的糖基转移酶的表达或正常表达的转移酶特异性的改变所诱导的。

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