Skip to main content
SpringerLink
Log in

Cartilage tumour progression is characterized by an increased expression of heparan sulphate 6O-sulphation-modifying enzymes

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fletcher CD, Unni KK, Mertens F (eds) (2002) World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. IARC, Lyon

    Google Scholar 

  2. Bovee JV, van den Broek LJ, Cleton-Jansen AM, Hogendoorn PC (2000) Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest 80:1925–1934

    Article  PubMed  CAS  Google Scholar 

  3. Hameetman L, Rozeman LB, Lombaerts M, Oosting J, Taminiau AH, Cleton-Jansen AM, Bovée JV, Hogendoorn PC (2006) Peripheral chondrosarcoma progression is accompanied by decreased Indian Hedgehog signalling. J Pathol 209:501–511

    Article  PubMed  CAS  Google Scholar 

  4. Schrage YM, Hameetman L, Szuhai K, Cleton-Jansen AM, Taminiau AH, Hogendoorn PC, Bovée JV (2009) Aberrant heparan sulfate proteoglycan localization, despite normal exostosin, in central chondrosarcoma. Am J Pathol 174:979–988

    Article  PubMed  CAS  Google Scholar 

  5. Ahn J, Ludecke H-J, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE (1995) Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genet 11:137–143

    Article  PubMed  CAS  Google Scholar 

  6. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, De Vries BB, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, Van den Ouweland AM, McGaughran J, Halley DJ, Willems P (1996) Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet 5:1547–1557

    Article  PubMed  CAS  Google Scholar 

  7. Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777

    Article  PubMed  CAS  Google Scholar 

  8. Rodgers KD, San Antonio JD, Jacenko O (2008) Heparan sulfate proteoglycans: a GAGgle of skeletal-hematopoietic regulators. Dev Dyn 237:2622–2642

    Article  PubMed  CAS  Google Scholar 

  9. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O'Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM (2011) IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol 224:334–343

    Article  PubMed  CAS  Google Scholar 

  10. Pansuriya TC, van Eijk R, d’Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, van Wezel T, Nord KH, Sangiorgi L, Toker B, Liegl-Atzwanger B, San-Julian M, Sciot R, Limaye N, Kindblom LG, Daugaard S, Godfraind C, Boon LM, Vikkula M, Kurek KC, Szuhai K, French PJ, Bovee JV (2011) Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 43:1256–1261

    Article  PubMed  CAS  Google Scholar 

  11. de Andrea CE, Hogendoorn PC (2012) Epiphyseal growth plate and secondary peripheral chondrosarcoma: the neighbours matter. J Pathol 226:219–228

    Article  PubMed  Google Scholar 

  12. de Andrea CE, Reijnders CM, Kroon HM, de Jong D, Hogendoorn PC, Szuhai K, Bovee JV (2012) Secondary peripheral chondrosarcoma evolving from osteochondroma as a result of outgrowth of cells with functional EXT. Oncogene 31:1095–1104

    Article  PubMed  Google Scholar 

  13. Backen AC, Cole CL, Lau SC, Clamp AR, McVey R, Gallagher JT, Jayson GC (2007) Heparan sulphate synthetic and editing enzymes in ovarian cancer. Br J Cancer 96:1544–1548

    Article  PubMed  CAS  Google Scholar 

  14. Tatrai P, Egedi K, Somoracz A, van Kuppevelt TH, Ten DG, Lyon M, Deakin JA, Kiss A, Schaff Z, Kovalszky I (2010) Quantitative and qualitative alterations of heparan sulfate in fibrogenic liver diseases and hepatocellular cancer. J Histochem Cytochem 58:429–441

    Article  PubMed  CAS  Google Scholar 

  15. Habuchi H, Tanaka M, Habuchi O, Yoshida K, Suzuki H, Ban K, Kimata K (2000) The occurrence of three isoforms of heparan sulfate 6-O-sulfotransferase having different specificities for hexuronic acid adjacent to the targeted N-sulfoglucosamine. J Biol Chem 275:2859–2868

    Article  PubMed  CAS  Google Scholar 

  16. Morimoto-Tomita M, Uchimura K, Werb Z, Hemmerich S, Rosen SD (2002) Cloning and characterization of two extracellular heparin-degrading endosulfatases in mice and humans. J Biol Chem 277:49175–49185

    Article  PubMed  CAS  Google Scholar 

  17. Dhoot GK, Gustafsson MK, Ai X, Sun W, Standiford DM, Emerson CP Jr (2001) Regulation of Wnt signaling and embryo patterning by an extracellular sulfatase. Science 293:1663–1666

    Article  PubMed  CAS  Google Scholar 

  18. Lamanna WC, Kalus I, Padva M, Baldwin RJ, Merry CL, Dierks T (2007) The heparanome–the enigma of encoding and decoding heparan sulfate sulfation. J Biotechnol 129:290–307

    Article  PubMed  CAS  Google Scholar 

  19. Pansuriya TC, Oosting J, Krenacs T, Taminiau AH, Verdegaal SH, Sangiorgi L, Sciot R, Hogendoorn PC, Szuhai K, Bovee JV (2011) Genome-wide analysis of Ollier disease: is it all in the genes? Orphanet J Rare Dis 6:2

    Article  PubMed  Google Scholar 

  20. Bovée JV, Cleton-Jansen AM, Kuipers-Dijkshoorn N, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC (1999) Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma. Genes Chrom Cancer 26:237–246

    Article  PubMed  Google Scholar 

  21. Grigolo B, Roseti L, Neri S, Gobbi P, Jensen P, Major EO, Facchini A (2002) Human articular chondrocytes immortalized by HPV-16 E6 and E7 genes: maintenance of differentiated phenotype under defined culture conditions. Osteoarthr Cartil 10:879–889

    Article  PubMed  CAS  Google Scholar 

  22. Gil-Benso R, Lopez-Gines C, Lopez-Guerrero JA, Carda C, Callaghan RC, Navarro S, Ferrer J, Pellin A, Llombart-Bosch A (2003) Establishment and characterization of a continuous human chondrosarcoma cell line, ch-2879: comparative histologic and genetic studies with its tumor of origin. Lab Invest 83:877–887

    PubMed  CAS  Google Scholar 

  23. Kunisada T, Miyazaki M, Mihara K, Gao C, Kawai A, Inoue H, Namba M (1998) A new human chondrosarcoma cell line (OUMS-27) that maintains chondrocytic differentiation. Int J Cancer 77:854–859

    Article  PubMed  CAS  Google Scholar 

  24. Reijnders CM, Waaijer CJ, Hamilton A, Buddingh EP, Dijkstra SP, Ham J, Bakker E, Szuhai K, Karperien M, Hogendoorn PC, Stringer SE, Bovee JV (2010) No haploinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas. Am J Pathol 177:1946–1957

    Article  PubMed  CAS  Google Scholar 

  25. Lai JP, Sandhu DS, Shire AM, Roberts LR (2008) The tumor suppressor function of human sulfatase 1 (SULF1) in carcinogenesis. J Gastrointest Cancer 39:149–158

    Article  PubMed  CAS  Google Scholar 

  26. Lemjabbar-Alaoui H, van Zante A, Singer MS, Xue Q, Wang YQ, Tsay D, He B, Jablons DM, Rosen SD (2010) Sulf-2, a heparan sulfate endosulfatase, promotes human lung carcinogenesis. Oncogene 29:635–646

    Article  PubMed  CAS  Google Scholar 

  27. Chen E, Stringer SE, Rusch MA, Selleck SB, Ekker SC (2005) A unique role for 6-O sulfation modification in zebrafish vascular development. Dev Biol 284:364–376

    Article  PubMed  CAS  Google Scholar 

  28. Smeds E, Habuchi H, Do AT, Hjertson E, Grundberg H, Kimata K, Lindahl U, Kusche-Gullberg M (2003) Substrate specificities of mouse heparan sulphate glucosaminyl 6-O-sulphotransferases. Biochem J 372:371–380

    Article  PubMed  CAS  Google Scholar 

  29. Tekotte H, Engel M, Margolis RU, Margolis RK (1994) Disaccharide composition of heparan sulfates: brain, nervous tissue storage organelles, kidney, and lung. J Neurochem 62:1126–1130

    Article  PubMed  CAS  Google Scholar 

  30. Toida T, Yoshida H, Toyoda H, Koshiishi I, Imanari T, Hileman RE, Fromm JR, Linhardt RJ (1997) Structural differences and the presence of unsubstituted amino groups in heparan sulphates from different tissues and species. Biochem J 322(Pt 2):499–506

    PubMed  CAS  Google Scholar 

  31. Warda M, Toida T, Zhang F, Sun P, Munoz E, Xie J, Linhardt RJ (2006) Isolation and characterization of heparan sulfate from various murine tissues. Glycoconj J 23:555–563

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Pathology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, L1-Q, 2300 RC, Leiden, The Netherlands

    Cathelijn J F Waaijer, Carlos E de Andrea, Jolieke G van Oosterwijk & Judith V M G Bovée

  2. Cardiovascular Medicine, School of Biomedicine, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre (CMFT), University of Manchester, 46 Grafton Street, Manchester, M13 9NT, UK

    Andrew Hamilton & Sally E Stringer

Authors
  1. Cathelijn J F Waaijer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos E de Andrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jolieke G van Oosterwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sally E Stringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Judith V M G Bovée
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Judith V M G Bovée.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waaijer, C.J.F., de Andrea, C.E., Hamilton, A. et al. Cartilage tumour progression is characterized by an increased expression of heparan sulphate 6O-sulphation-modifying enzymes. Virchows Arch 461, 475–481 (2012). https://doi.org/10.1007/s00428-012-1300-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1300-5

Keywords

Search

Navigation