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

Journal article

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.

Authors: van Oosterwijk, J; Meijer, D; Ruler, v; van den Akker, B; Oosting, J

• Publication status: Published
• Journal: American journal of pathology
• Volume: 182
• Issue: 4
• Pages: 1347-1356
• Publication date: 2013-04-01
• DOI: 10.1016/j.ajpath.2012.12.036
• EISSN: 1525-2191
• ISSN: 0002-9440
• Language: English
• Keywords: Humans; Immunohistochemistry; Antineoplastic Agents; Transforming Growth Factor beta; Tissue Fixation; Signal Transduction; Paraffin Embedding; Female; Cell Dedifferentiation; Sarcoma, Clear Cell; Male; Aged, 80 and over; Proto-Oncogene Proteins c-bcl-2; Neoplasm Proteins; Young Adult; Molecular Targeted Therapy; Chondrosarcoma, Mesenchymal; Drug Resistance, Neoplasm; Middle Aged; Adult; Aged