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Background: Mutations and loss of the von Hippel-Lindau (VHL) tumor suppressor gene are associated with most renal cancers as well as several other types of human tumors, but the potential role of the VHL protein (pVHL) in patients with chondrosarcoma has not been characterized. The purpose of the present study was to investigate the expression profiles of pVHL in chondrosarcoma and its association with clinicopathologic parameters, Bax expression, the apoptosis index, and overall survival of patients with chondrosarcoma., Methods: The messenger RNA (mRNA) and protein levels of VHL in fresh specimens from eight chondrosarcomas were studied with use of real-time polymerase chain reaction and Western blot, respectively. The protein expression of VHL and Bax was investigated by means of immunohistochemical analysis of paraffin-embedded clinical specimens from seventeen benign cartilage tumors and thirty-four chondrosarcomas. The apoptosis index in chondrosarcoma was examined by means of the TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assay. Curves for overall survival were drawn according to the Kaplan-Meier method, and differences were analyzed with the log-rank test. The association of pVHL expression with the clinicopathologic parameters, Bax expression, apoptosis index, and overall survival for patients with chondrosarcoma was also analyzed., Results: Levels of VHL protein (p = 0.005) and mRNA (p = 0.008) were significantly reduced in chondrosarcoma tissues as compared with the paired adjacent normal tissues. Immunohistochemical analysis showed decreased pVHL in a significantly higher proportion of chondrosarcomas (64.7%) than benign cartilage tumors (29.4%). pVHL expression was positively correlated with Bax expression and the apoptosis index in chondrosarcoma. Longitudinal studies of a cohort of patients with chondrosarcomas showed that decreased pVHL expression significantly correlated with increased tumor grade (p = 0.026) but was not independently predictive of overall survival., Conclusions: Reduced pVHL expression was associated with decreased apoptosis and increasing chondrosarcoma grade, but the relationship between these findings and chondrosarcoma pathogenesis requires further study.

Background: Hypoxia inducible factor (HIF)-2α is an important transcription factor that contributes to tumor proliferation and progression. Beclin 1 is a key mediator of autophagy, and dysfunction of Beclin 1 is implicated in tumorigenicity. This study was designed to investigate the expression patterns of HIF-2α and Beclin 1 and to clarify their clinical significance in chondrosarcoma., Methods: The mRNA and protein levels of HIF-2α and Beclin 1 in chondrosarcoma and the corresponding nontumor tissues were analyzed by real-time polymerase chain reaction and Western blot, respectively. The protein expression of HIF-2α and Beclin 1 was investigated by immunohistochemistry, and their associations with clinicopathological factors and overall survival were evaluated., Results: HIF-2α was remarkably elevated, whereas Beclin 1 was significantly reduced in chondrosarcoma compared with the corresponding nontumor tissues. High HIF-2α level and negative Beclin 1 expression were 52.9% and 58.8% in chondrosarcoma specimens, respectively. HIF-2α and Beclin 1 were associated with histological grade and Musculoskeletal Tumor Society stage. There was a significant inverse relationship between HIF-2α and Beclin 1. HIF-2α and Beclin 1 had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that Beclin 1 was an independent prognostic factor for overall survival of patients with chondrosarcoma., Conclusions: Elevated HIF-2α levels associated with low Beclin 1 expression play a role in the development of chondrosarcoma. Beclin 1 can serve as a novel biomarker to predict survival of chondrosarcoma patients, and may represent a potential therapeutic target.

Hypoxia-inducible factor (HIF)-1α is a key nuclear transcription factor that regulates the cellular response to hypoxia, and is important for solid tumor growth and survival. However, the underlying role of HIF-1α in human chondrosarcoma has not been well characterized. This study aims to investigate the expression patterns of HIF-1α in chondrosarcoma, and its association with clinicopathologic features, Bcl-xL expression, apoptosis index (AI), and overall survival of patients with chondrosarcoma. Our results shown that the protein levels of HIF-1α were increased, and the mRNA and protein levels of Bcl-xL were also increased in SW1353 cells under hypoxic conditions. In eight patients with chondrosarcoma, increased expression of HIF-1α and Bcl-xL was detected in chondrosarcoma tissues compared with the paired adjacent normal tissues. Of 34 archival specimens of chondrosarcomas, 20 (58.8%) showed high HIF-1α protein expression as compared to benign cartilage tumors. Increased HIF-1α expression was correlated with a higher pathological grade and MSTS stage of chondrosarcoma. Moreover, HIF-1α expression was significantly associated with Bcl-xL expression and AI. More significantly, the survival rate of patients with HIF-1α high tumors was significantly lower than that of patients with HIF-1α low tumors. These findings suggest that increased HIF-1α levels mediated up-regulation of Bcl-xL play a prominent role in evasion of apoptosis and tumor progression, and can be predictive for the prognosis in human chondrosarcoma., (Copyright © 2010 Orthopaedic Research Society.)

Background and Objectives: Programmed Cell Death 5 (PDCD5) is a novel apoptosis-related gene and deregulation of PDCD5 is involved in tumorigenicity. This study was designed to investigate the expression level of PDCD5 and to clarify its clinical significance in chondrosarcoma., Methods: The mRNA and protein levels of PDCD5 in chondrosarcoma and matched corresponding non-tumor tissues were evaluated by real-time PCR and Western blot, respectively. The expression of PDCD5 protein was investigated by immunohistochemistry assays in chondrosarcoma, and its association with clinicopathologic factors and overall survival was also analyzed., Results: The mRNA and protein levels of PDCD5 were significantly decreased in chondrosarcoma compared with corresponding non-tumor tissues. Low expression of PDCD5 protein was 61.8% (21/34) in chondrosarcomas, as compared 12.5% (1/8) in normal bones, as well as compared 23.5% (4/17) in benign cartilage tumors. PDCD5 expression was correlated with anatomical location and histological grade. The survival rate of patients with low-PDCD5 tumors was lower than that of patients with high-PDCD5 tumors. Multivariate analysis revealed that the downregulated expression of PDCD5 was an independent prognostic factor for overall survival., Conclusions: PDCD5 is downregulated in chondrosarcoma and might be an independent prognostic factor for overall survival of chondrosarcoma patients., (2010 Wiley-Liss, Inc.)

Clinical management of chondrosarcoma remains a challenging problem, largely due to the toxicity and resistance of this tumor to conventional chemotherapy. Programmed Cell Death 5 (PDCD5) is a protein that accelerates apoptosis in different cell types in response to various stimuli, and has been shown to be down-regulated in many cancer tissues. In this study, mRNA and protein levels of PDCD5 were found to be up-regulated in cisplatin-treated SW1353 chondrosarcoma cells compared with untreated cells. Recombinant human PDCD5 (rhPDCD5) was also shown to sensitize chondrosarcoma cells to cisplatin-based chemotherapy, with inhibition of cell growth and apoptosis detected both in vitro and in vivo. Increased expression of Bax and decreased expression of Bcl-2 were also observed, along with release of cytochrome c from mitochondria into the cytosol. Additionally, cleavage of caspase-9 and caspase-3, as well as the cleavage of poly (ADP-ribose) polymerase (PARP), were detected, suggesting that sensitization of chondrosarcoma cells involves the intrinsic mitochondrial apoptosis pathway. In vivo, the treatment of a xenograft model of chondrosarcoma with rhPDCD5 and cisplatin significantly inhibited tumor cell proliferation and induced apoptosis compared to treatment with cisplatin alone. Overall, these data provide a theoretical basis for the administration of rhPDCD5 and cisplatin for the treatment of patients with chondrosarcoma.