title: 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: Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Jolieke G
authors: JG
authors: van Oosterwijk
authors: Danielle
authors: D
authors: Meijer
authors: Maayke A J H
authors: MA
authors: van Ruler
authors: Brendy E W M
authors: BE
authors: van den Akker
authors: Jan
authors: J
authors: Oosting
authors: Tibor
authors: T
authors: Krenács
authors: Piero
authors: P
authors: Picci
authors: Adrienne M
authors: AM
authors: Flanagan
authors: Bernadette
authors: B
authors: Liegl-Atzwanger
authors: Andreas
authors: A
authors: Leithner
authors: Nick
authors: N
authors: Athanasou
authors: Søren
authors: S
authors: Daugaard
authors: Pancras C W
authors: PC
authors: Hogendoorn
authors: Judith V M G
authors: JV
authors: Bovée
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054337:Cell Dedifferentiation / Q000187:drug effects*; D018211:Chondrosarcoma, Mesenchymal / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism; D016612:Paraffin Embedding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018227:Sarcoma, Clear Cell / Q000145:classification / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D016707:Tissue Fixation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta