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

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.

• Authors: 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
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 4 Pg. 1347-56 (Apr 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23415961 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Neoplasm Proteins
• Proto-Oncogene Proteins c-bcl-2
• Transforming Growth Factor beta

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Dedifferentiation (drug effects)
• Chondrosarcoma, Mesenchymal (classification, drug therapy, metabolism, pathology)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Immunohistochemistry
• Male
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Proteins (metabolism)
• Paraffin Embedding
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism)
• Sarcoma, Clear Cell (classification, drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Tissue Fixation
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• Young Adult