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, T. Krenács, Piero Picci, Adrienne M. Flanagan, Bernadette Liegl-Atzwanger, Andreas Leithner, Nick Athanasou, Søren Daugaard, Pancras C W Hogendoorn, Judith V M G Bovée

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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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Chondrosarcoma
Therapeutics
Mesenchymal Chondrosarcoma
Heparan Sulfate Proteoglycans
Growth Plate
Plasminogen Activator Inhibitor 1
Doxorubicin
Cisplatin
Proteins
Immunohistochemistry
Cell Line

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFβ as potential targets. / Van Oosterwijk, Jolieke G.; Meijer, Danielle; Van Ruler, Maayke A J H; Van Den Akker, Brendy E W M; Oosting, Jan; Krenács, T.; Picci, Piero; Flanagan, Adrienne M.; Liegl-Atzwanger, Bernadette; Leithner, Andreas; Athanasou, Nick; Daugaard, Søren; Hogendoorn, Pancras C W; Bovée, Judith V M G.

In: American Journal of Pathology, Vol. 182, No. 4, 04.2013, p. 1347-1356.

Research output: Contribution to journalArticle

Van Oosterwijk, JG, Meijer, D, Van Ruler, MAJH, Van Den Akker, BEWM, Oosting, J, Krenács, T, Picci, P, Flanagan, AM, Liegl-Atzwanger, B, Leithner, A, Athanasou, N, Daugaard, S, Hogendoorn, PCW & Bovée, JVMG 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, vol. 182, no. 4, pp. 1347-1356. https://doi.org/10.1016/j.ajpath.2012.12.036
Van Oosterwijk, Jolieke G. ; Meijer, Danielle ; Van Ruler, Maayke A J H ; Van Den Akker, Brendy E W M ; Oosting, Jan ; Krenács, T. ; Picci, Piero ; Flanagan, Adrienne M. ; Liegl-Atzwanger, Bernadette ; Leithner, Andreas ; Athanasou, Nick ; Daugaard, Søren ; Hogendoorn, Pancras C W ; Bovée, Judith V M G. / Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFβ as potential targets. In: American Journal of Pathology. 2013 ; Vol. 182, No. 4. pp. 1347-1356.
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