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.
Highlights
Chondrosarcoma is a malignant cartilage-forming tumor accounting for 20% of all malignant bone tumors.[1]
An siRNA screen targeting 51 apoptosis-related genes revealed that HRK (Harakiri, BCL2 Interacting Protein), BIRC5 (Baculoviral IAP Repeat Containing 5), BCL2L1 (B-cell/Lymphoma 2 like 1), BCL-10 (B-cell/Lymphoma 10) and CRADD (CASP2 And RIPK1 Domain Containing Adaptor With Death Domain) were essential genes in the JJ012 chondrosarcoma cell line (Figure 1a)
Nuclear survivin expression is associated with p53 overexpression in high-grade conventional chondrosarcoma As p53 is a known effector of survivin expression,[17] we investigated a possible correlation between p53 overexpression and survivin expression using the conventional chondrosarcoma tissue micro array (TMA). p53 overexpression was observed in 0/50 grade I, 20/41 grade II and 9/17 grade III conventional chondrosarcomas (Figures 3a and b)
Summary
Chondrosarcoma is a malignant cartilage-forming tumor accounting for 20% of all malignant bone tumors.[1] Chondrosarcomas represent a heterogeneous group as different histological subtypes are recognized, including conventional, dedifferentiated, mesenchymal, clear cell and periosteal chondrosarcoma. The conventional subtype is most frequent (85%)[1] and can be further categorized into central chondrosarcoma (485%) (in medullar cavity) and peripheral chondrosarcoma (at the bone surface).[2]. Atypical cartilaginous tumors (ACT) (previously referred to as grade I chondrosarcomas) show low cellularity and are locally aggressive, but do not metastasize. High-grade chondrosarcomas comprise grade II and III chondrosarcomas and show higher cellularity, mitoses and less cartilaginous matrix. Histological grading represents the most important prognostic factor; patients with atypical cartilaginous tumors show a 10-year overall survival rate of 83%, patients with grade II tumors show
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