Abstract
BackgroundConventional chondrosarcomas are malignant cartilage tumors considered radioresistant. Nevertheless, retrospective series show a small but significant survival benefit for patients with locally advanced disease treated with radiotherapy. And, in daily practice when considered inoperable their irradiation is an accepted indication for proton beam radiotherapy. Therefore, we investigated the sensitivity of chondrosarcoma cell lines and -tissue samples towards radiotherapy and screened for biomarkers to identify predictors of radiosensitivity.MethodsProliferation and clonogenic assays were performed in chondrosarcoma cell lines after γ-radiation in combination with mutant IDH1 inhibitor AGI-5198. In addition, glutathione levels were measured using mass spectrometry. Chondrosarcoma tumor explants were irradiated after which γ-H2AX foci were counted. Mutation analysis was performed using the Ion AmpliSeq™ Cancer Hotspot Panel and immunohistochemical staining’s were performed for P-S6, LC-3B, P53, Bcl-2, Bcl-xl and Survivin. Results were correlated with the number of γ-H2AX foci.ResultsChondrosarcoma cell lines were variably γ-radiation resistant. No difference in radiosensitivity, nor glutathione levels was observed after treatment with AGI-5198. Irradiated chondrosarcoma patient tissue presented a variable increase in γ-H2AX foci compared to non-radiated tissue. Samples were divided into two groups, high and low radioresistant, based on the amount of γ-H2AX foci. All four highly resistant tumors exhibited mutations in the pRb pathway, while none of the less radioresistant tumors showed mutations in these genes.ConclusionsChondrosarcoma cell lines as well as primary tumors are variably radioresistant, particularly in case of a defective Rb pathway. Whether selection for radiotherapy can be based upon an intact Rb pathway should be further investigated.
Highlights
Conventional chondrosarcomas are malignant cartilage tumors considered radioresistant
We focused on central chondrosarcomas, as these are of highest prevalence
Chondrosarcoma cell lines are variably resistant to γ‐radiation Clonogenic assay SF2 values suggested that JJ012 cells (SF2 0.55) were more radiosensitive compared to SW1353 (SF2 0.88) (Fig. 1a)
Summary
Conventional chondrosarcomas are malignant cartilage tumors considered radioresistant. Chondrosarcomas are a heterogeneous group of cartilage producing tumors of which the most prevalent subtype is conventional chondrosarcoma (85%). Conventional chondrosarcoma can be subdivided into three histological grades, representing the most important prognostic factor. Probability of surviving 10 years is about 64% for grade II chondrosarcomas and about 29% for grade III chondrosarcomas [1,2,3]. Based on their location conventional chondrosarcoma can be further subdivided into central (85%) and peripheral de Jong et al Clin Sarcoma Res (2019) 9:9
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