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Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

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  • 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
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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.
OriginalsprogEngelsk
TidsskriftAmerican Journal of Pathology
Vol/bind182
Udgave nummer4
Sider (fra-til)1347-56
Antal sider10
ISSN0002-9440
DOI
StatusUdgivet - apr. 2013

ID: 41120802