Department of Pathology, Leiden University Medical Center, Albinusdreef 2, L1-Q, 2300 RC Leiden, The Netherlands.
Virchows Arch. 2012 Oct;461(4):475-81. doi: 10.1007/s00428-012-1300-5. Epub 2012 Aug 18.
Chondrosarcomas are malignant cartilage-forming tumours that can arise centrally (in the medulla) or peripherally (at the surface) of the bone. They are classified into three histological grades which correspond to the clinical severity. Previous studies by our group have shown altered signal transduction of the fibroblast growth factor and Wnt signalling pathways during peripheral chondrosarcoma progression. Heparan sulphate (HS) is a glycosaminoglycan that facilitates receptor binding of multiple growth factors, in which the sulphation of 6O position plays a pivotal role. 6O-Sulphation occurs through three HS 6O-sulphotransferases (HS6ST1-3) and is fine-tuned by two endosulphatases (SULF1-2) that remove 6O-sulphate groups. We have investigated whether the expression of HS6STs and SULFs changes during chondrosarcoma progression and have determined 6O-sulphation levels in two chondrosarcoma cell lines. Immunohistochemistry on tissue microarrays of chondrosarcomas showed that HS6ST3 and SULF1 were highly expressed in most chondrosarcomas, whereas SULF2 expression was absent in most cases. HS6ST1 and HS6ST2 expression are significantly increased during chondrosarcoma progression, which suggest that 6O-sulphation is increased during progression. This was confirmed in one grade III chondrosarcoma cell line, which showed a dramatically increased 6O-sulphation compared to an articular chondrocyte cell line by HPLC; another cell line showed an increased expression of one 6O-sulphated HS disaccharide. In conclusion, our results show increased HS6ST1 and HS6ST2 expression during chondrosarcoma progression and increased HS 6O-sulphation in vitro. As 6O-sulphation plays an important role in signal transduction, altered HS6ST expression might be associated with changes in signal transduction pathways in chondrosarcoma progression.
软骨肉瘤是一种恶性的软骨形成肿瘤，可发生在骨的中心（骨髓）或外围（表面）。它们分为三个组织学等级，与临床严重程度相对应。我们小组的先前研究表明，在周围性软骨肉瘤进展过程中，成纤维细胞生长因子和 Wnt 信号通路的信号转导发生改变。硫酸乙酰肝素（HS）是一种糖胺聚糖，可促进多种生长因子的受体结合，其中 6O 位的硫酸化起着关键作用。6O-硫酸化通过三个 HS6O-硫酸转移酶（HS6ST1-3）发生，并通过两个内切硫酸酯酶（SULF1-2）进行微调，后者去除 6O-硫酸基团。我们研究了 HS6STs 和 SULFs 的表达是否在软骨肉瘤进展过程中发生变化，并确定了两种软骨肉瘤细胞系中的 6O-硫酸化水平。对软骨肉瘤组织微阵列的免疫组织化学分析表明，HS6ST3 和 SULF1 在大多数软骨肉瘤中高度表达，而 SULF2 在大多数情况下表达缺失。HS6ST1 和 HS6ST2 的表达在软骨肉瘤进展过程中显著增加，这表明 6O-硫酸化在进展过程中增加。这在一个 3 级软骨肉瘤细胞系中得到了证实，与关节软骨细胞系相比，该细胞系的 6O-硫酸化程度明显增加，通过 HPLC 证实；另一个细胞系显示一种 6O-硫酸化的 HS 二糖表达增加。总之，我们的结果表明，在软骨肉瘤进展过程中 HS6ST1 和 HS6ST2 的表达增加，并且体外 HS 6O-硫酸化增加。由于 6O-硫酸化在信号转导中起重要作用，因此 HS6ST 表达的改变可能与软骨肉瘤进展中信号转导途径的变化有关。
