Screening for Potential Targets for Therapy in Mesenchymal, Clear Cell, and Dedifferentiated Chondrosarcoma Reveals Bcl-2 Family Members and TGF beta as Potential Targets
| Autor: | Adrienne M. Flanagan, Nicholas A. Athanasou, Jan Oosting, Brendy E.W.M. van den Akker, Judith V.M.G. Bovée, Pancras C.W. Hogendoorn, Maayke A. J. H. van Ruler, Jolieke G. van Oosterwijk, Andreas Leithner, Piero Picci, Tibor Krenács, Søren Daugaard, Danielle Meijer, Bernadette Liegl-Atzwanger |
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| Přispěvatelé: | Molecular Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male musculoskeletal diseases Pathology medicine.medical_specialty Tissue Fixation animal structures Antineoplastic Agents Pathology and Forensic Medicine Young Adult Transforming Growth Factor beta medicine Humans Molecular Targeted Therapy Cellular localization Aged Aged 80 and over Tissue microarray Paraffin Embedding biology Mesenchymal stem cell Bcl-2 family Transforming growth factor beta Cell Dedifferentiation Middle Aged medicine.disease musculoskeletal system Immunohistochemistry Neoplasm Proteins Proto-Oncogene Proteins c-bcl-2 Drug Resistance Neoplasm embryonic structures biology.protein Cancer research Chondrosarcoma Mesenchymal Female Sarcoma Sarcoma Clear Cell Chondrosarcoma Clear cell Signal Transduction |
| Zdroj: | American Journal of Pathology, 182(4), 1347-1356 American Journal of Pathology, 182(4), 1347-1356. Elsevier Inc. |
| ISSN: | 0002-9440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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