Cartilage tumour progression is characterized by an increased expression of heparan sulphate 6O-sulphation-modifying enzymes
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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.
KeywordsChondrosarcoma Heparan sulphate 6O-Sulphation Bone tumours Immunohistochemistry
We thank Andrea Facchini (Istituto Ortopedico Rizzoli, Bologna, Italy) for the donation of the LBPVA cell line, Antonio Llombart-Bosch (Valencia University, Spain) for the CH2879 cell line and Toshiyuki Kunisada (Okayama University Medical School, Japan) for the OUMS27 cell line. We would also like to thank Armin Walter (Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands) for kindly providing patient samples. We would also like to gratefully acknowledge Pancras Hogendoorn, Christianne Reijnders, Steve Rosen (University of California, San Diego, CA, USA) and Jacob van den Born (University Medical Center Groningen, The Netherlands) for their fruitful discussion. Lastly, we would like to thank Klaas van der Ham for his photographic assistance and Inge Briaire-de Bruijn and Dorien van der Geest for their expert technical assistance. This work was supported by The Netherlands Organisation for Scientific Research (917-76-315 to JVMGB and CJFW) and the European Network of Excellence EuroBoNet grant number 018814 (LSHC-CT-2006-018814 to CJFW and CEdA).
Conflict of interest
The authors declare that they have no conflicts of interest.
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