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.
American Journal of Pathology, 2013, Vol 182, Issue 4, p. 1347-56
Journal Article; Research Support, Non-U.S. Gov't; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cell Dedifferentiation; Chondrosarcoma, Mesenchymal; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Paraffin Embedding; Proto-Oncogene Proteins c-bcl-2; Sarcoma, Clear Cell; Signal Transduction; Tissue Fixation; Transforming Growth Factor beta; Young Adult