Fabris Dragana, Rožman Marko, Sajko Tomislav, Vukelić Željka
Department of Chemistry and Biochemistry, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
Department of Physical Chemistry, Ruđer Bošković Institute, 1000 Zagreb, Croatia.
Biochimie. 2017 Jun;137:56-68. doi: 10.1016/j.biochi.2017.03.001. Epub 2017 Mar 10.
Tumor cells are characterized by aberrant glycosylation of the cell surface glycoconjugates. Gangliosides are sialylated glycosphingolipids highly abundant in neural tissue and considered as tumor markers and therapeutic targets. In this study, a detailed characterization of native ganglioside mixtures from glioblastoma multiforme, corresponding peritumoral tissue and healthy human brain was performed using mass spectrometry and high performance thin layer chromatography in order to elucidate their roles as tumor-associated antigens. Distinctive changes in ganglioside expression were determined in glioblastoma compared to healthy brain tissue showing 5 times lower total ganglioside content and higher abundance of simple gangliosides. Glioblastoma gangliosides were characterized by highly diverse ceramide composition with fatty acyl chains varying from 16 to 24 carbon atoms, while in normal and peritumoral tissue mostly C18 chains were found. The most abundant ganglioside in glioblastoma was GD3 (d18:1/18:0), followed by GD3 (d18:1/24:0) that was exclusively detected in glioblastoma tissue. Peritumoral tissue expressed higher abundance of GD3- and nLM1/GM1-species while lower GT1-species vs. normal brain. O-Ac-GD1, known as neurostatin, was detected in normal and peritumoral tissue, but not in glioblastoma. O-Ac-GD3 species were found exclusively in glioblastoma; MS structural characterization of the isomeric form possessing the O-acetylation at the inner sialic acid residue confirmed our previous finding that this isomer is glioma-associated. This, to our knowledge, the most detailed characterization of ganglioside composition in glioblastoma and peritumoral tissue, especially addressing the ceramide variability and O-acetylation of tumor-associated gangliosides, could contribute to recognition of new molecular targets for glioblastoma treatment and sub-classification.
肿瘤细胞的特征是细胞表面糖缀合物的异常糖基化。神经节苷脂是在神经组织中高度丰富的唾液酸化糖鞘脂，被认为是肿瘤标志物和治疗靶点。在本研究中，使用质谱和高效薄层色谱对多形性胶质母细胞瘤、相应的瘤周组织和健康人脑的天然神经节苷脂混合物进行了详细表征，以阐明它们作为肿瘤相关抗原的作用。与健康脑组织相比，多形性胶质母细胞瘤中神经节苷脂表达有明显变化，总神经节苷脂含量低5倍，简单神经节苷脂丰度更高。多形性胶质母细胞瘤神经节苷脂的特征是神经酰胺组成高度多样，脂肪酰链的碳原子数从16到24不等，而在正常和瘤周组织中大多发现的是C18链。多形性胶质母细胞瘤中最丰富的神经节苷脂是GD3（d18:1/18:0），其次是仅在多形性胶质母细胞瘤组织中检测到的GD3（d18:1/24:0）。与正常脑相比，瘤周组织中GD3和nLM1/GM1种类的丰度更高，而GT1种类的丰度更低。在正常和瘤周组织中检测到了被称为神经抑素的O - Ac - GD1，但在多形性胶质母细胞瘤中未检测到。O - Ac - GD3种类仅在多形性胶质母细胞瘤中发现；对在内侧唾液酸残基处具有O - 乙酰化的异构体形式的质谱结构表征证实了我们之前的发现，即这种异构体与胶质瘤相关。据我们所知，这是对多形性胶质母细胞瘤和瘤周组织中神经节苷脂组成最详细的表征，特别是针对肿瘤相关神经节苷脂的神经酰胺变异性和O - 乙酰化，这可能有助于识别多形性胶质母细胞瘤治疗和亚分类的新分子靶点。
