Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFβ as potential targets

Jolieke G. Van Oosterwijk, Danielle Meijer, Maayke A J H Van Ruler, Brendy E W M Van Den Akker, Jan Oosting, Tibor Krenács, Piero Picci, Adrienne M. Flanagan, Bernadette Liegl-Atzwanger, Andreas Leithner, Nick Athanasou, Søren Daugaard, Pancras C W Hogendoorn, Judith V M G Bovée

Research output: Contribution to journalArticle

Abstract

The mesenchymal, clear cell, and dedifferentiated chondrosarcoma subtypes are extremely rare, together constituting 10% to 15% of all chondrosarcomas. Their poor prognosis and lack of efficacious treatment emphasizes the need to elucidate the pathways playing a pivotal role in these tumors. We constructed tissue microarrays containing 42 dedifferentiated, 23 clear cell, and 23 mesenchymal chondrosarcomas and performed immunohistochemistry to study the expression of growth plate-signaling molecules and molecules shown to be involved in conventional chondrosarcoma. We observed high expression of SOX-9 and FGFR-3, as well as aberrant cellular localization of heparan sulfate proteoglycans, in all subtypes. TGFβ signaling through p-SMAD2 and PAI-1 was highly active in all chondrosarcoma subtypes, which suggests that TGFβ inhibitors as a possible therapeutic strategy in rare chondrosarcoma subtypes. As in conventional chondrosarcoma, antiapoptotic proteins (Bcl-2, and/or Bcl-xl) were highly expressed in all subtypes. Inhibition with the BH-3 mimetic ABT-737 rendered dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin. Our data indicate that antiapoptotic proteins may play an important role in chemoresistance, suggesting a promising role for targeting Bcl-2 family members in chondrosarcoma treatment, irrespective of the subtype.

Original languageEnglish
Pages (from-to)1347-1356
Number of pages10
JournalAmerican Journal of Pathology
Volume182
Issue number4
DOIs
Publication statusPublished - Apr 2013

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Van Oosterwijk, J. G., Meijer, D., Van Ruler, M. A. J. H., Van Den Akker, B. E. W. M., Oosting, J., Krenács, T., Picci, P., Flanagan, A. M., Liegl-Atzwanger, B., Leithner, A., Athanasou, N., Daugaard, S., Hogendoorn, P. C. W., & Bovée, J. V. M. G. (2013). Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFβ as potential targets. American Journal of Pathology, 182(4), 1347-1356. https://doi.org/10.1016/j.ajpath.2012.12.036