title: Targeting survivin as a potential new treatment for chondrosarcoma of bone.
abstract: Chondrosarcomas are malignant cartilage-forming bone tumors, which are intrinsically resistant to chemo- and radiotherapy, leaving surgical removal as the only curative treatment option. Therefore, our aim was to identify genes involved in chondrosarcoma cell survival that could serve as a target for therapy. siRNA screening for 51 apoptosis-related genes in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as essential for chondrosarcoma survival. Using immunohistochemistry, nuclear as well as cytoplasmic survivin expression was analyzed in 207 chondrosarcomas of different subtypes. Nuclear survivin has been implicated in cell-cycle regulation while cytoplasmic localization is important for its anti-apoptotic function. RT-PCR was performed to determine expression of the most common survivin isoforms. Sensitivity to YM155, a survivin inhibitor currently in phase I/II clinical trial for other tumors, was examined in 10 chondrosarcoma cell lines using viability assay, apoptosis assay and cell-cycle analysis. Survivin expression was found in all chondrosarcoma patient samples. Higher expression of nuclear and cytoplasmic survivin was observed with increasing histological grade in central chondrosarcomas. Inhibition of survivin using YM155 showed that especially TP53 mutant cell lines were sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather, YM155 treatment resulted in a block in S phase in two out of three chondrosarcoma cell lines, indicating that survivin is more involved in cell-cycle regulation than in apoptosis. Thus, survivin is important for chondrosarcoma survival and chondrosarcoma patients might benefit from survivin inhibition using YM155, for which TP53 mutational status can serve as a predictive biomarker.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: van Oosterwijk
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Kruisselbrink
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: I H
authors.initials: IH
authors.lastname: Briaire-de Bruijn
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.|First Department of Pathology, Department of Clinical-laboratory Studies, Athens University Medical School, Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Agrogiannis
authors.affiliation: Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Z
authors.initials: Z
authors.lastname: Baranski
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A H G
authors.initials: AH
authors.lastname: Cleven
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: A-M
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: van de Water
authors.affiliation: Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: E H J
authors.initials: EH
authors.lastname: Danen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J V M G
authors.initials: JV
authors.lastname: Bovée