Impact of RANK signalling on survival and chemotherapy response in osteosarcoma

Bagó-Horváth, Zsuzsanna; Schmid, Katharina; Nagy-Bojarszky, Katalin; Funovics, Philipp T.; Sulzbacher, Irene

doi:10.1097/pat.0000000000000116

Cited by 38 publications

(45 citation statements)

References 32 publications

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“…The RANK/RANKL system induces osteolytic bone lesions, and blocking of this system prevents bone destruction (4)(5)(6)(7)(8)(9)(10). The results of the present study confirm previous data indicating that the chemotherapy responsiveness of patients with tumours that are RANK positive is equal to that of patients with RANK-negative tumours, whereas RANK-positive tumours are associated with a significantly higher mortality rate (11). A significantly higher mortality rate was detected amongst patients with RANK-positive osteosarcoma, but no differences were detected in the response to chemotherapy or rate of metastases.…”

Section: Discussionsupporting

confidence: 82%

“…In osteosarcoma, a pre-chemotherapy stratification of patients based on prognostic factors may aid the identification of non-responders at the initial stage and therefore increase therapeutic success. Multiple markers have been evaluated with respect to their prognostic value (3,11,(14)(15)(16)(17)(18). One of these markers is the RANK/RANKL cascade, which has a crucial role in mediating bone resorption.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study revealed poor patient prognosis in RANK-positive osteosarcomas, and suggested further investigations which were undertaken in the current study (11).…”

Section: Introductionmentioning

confidence: 99%

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Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Trieb

Windhager

2015

Oncology Letters

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Abstract. Receptor activator of nuclear factor κB (RANK), a member of the tumour necrosis factor family, is activated by its ligand and regulates the differentiation of osteoclasts and dendritic cells. Local growth of osteosarcoma involves destruction of the host bone by osteoclasts and proteolytic mechanisms. Although the prognosis of patients with osteosarcoma has been improved by advances in chemotherapy over the last four decades, the issues of non-responders, and the lack of effective prognostic markers have remained. The present study aimed to investigate the prognostic and predictive value of RANK expression in human osteosarcoma. The expression of RANK was immunohistochemically evaluated in biopsies of 43 patients (mean age 25.4 years) with high-grade osteosarcoma, and was found to be correlated with histological response to chemotherapy, disease-free status and overall survival. RANK expression was detected in eight of the 43 osteosarcoma specimens (18%), whereas the remaining specimens were negative for RANK. A statistically significant correlation was detected between RANK expression and the overall survival of patients. A total of 7/8 patients with RANK-expressing tumours succumbed to the disease (88% mortality rate amongst patients with RANK-positive tumours vs. 37% with RANK-negative tumours; P<0.05). No significant difference was found when comparing RANK expression status with response to chemotherapy; 50% of RANK-positive patients exhibited a poor response to chemotherapy, compared with 66% in the RANK negative group. In addition, the appearance of metastases was not correlated with RANK expression status (38% metastases in RANK-positive tumours vs. 34% in RANK-negative tumours). In conclusion, the results of the present study suggested that RANK expression is likely to be of prognostic, but not of predictive, value.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Trieb

Windhager

2015

Oncology Letters

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“…The cell concentration was adjusted to 1x10 5 /ml and seeded in 6-well plates. Each well was provided with 2 ml cell solution and the cells were cultured in a 5% CO 2 incubator at 37˚C.…”

Section: Flow Cytometry For the Detection Of The Cell Cycle In Transfmentioning

confidence: 99%

“…Osteosarcoma, the most common primary malignant tumor, has exhibited a high prevalence in the past 20 years, therefore, the establishment of novel chemotherapy drugs for osteosarcoma is urgently required (5)(6)(7). Approximately 900 novel cases are diagnosed each year in the USA (8,9).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-126 enhances the sensitivity of osteosarcoma cells to cisplatin and methotrexate

Jiang

Cheng

2015

Oncology Letters

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Abstract. The establishment of novel chemotherapy drugs for osteosarcoma is urgently required, and the mechanisms and effects of cisplatin (DDP) and methotrexate (MTX) in the current treatment of osteosarcoma have not been fully elucidated. The present study aimed to observe the effect of DDP, MTX and rapamycin on osteosarcoma cell proliferation and apoptosis, and to investigate the association between miR-126 and the effects of DDP and MTX in osteosarcoma cells. miR-126-overexpressing and -silencing lentiviral vectors were constructed, and MG63 and U-2 OS osteosarcoma cells were infected. An MTT assay was conducted to detect transfected cell proliferation, and the effects of the chemotherapy drugs on transfected cell apoptosis were detected by flow cytometry. The cell cycle of the transfected cells was analyzed via flow cytometry. As the miR-126-overexpressing and -silencing osteosarcoma cell lines were successfully constructed, it was observed that DDP and MTX inhibited osteosarcoma cell proliferation. With the decreased expression of miR-126, the sensitivity of osteosarcoma cells to DDP and MTX was reduced at the same concentration. The flow cytometry suggested that DDP and MTX could promote the apoptosis of osteosarcoma cells with overexpressed miR-126, whereas they could not significantly impact the apoptosis of the miR-126-silenced osteosarcoma cells. Meanwhile, DDP inhibited the cell cycle of the miR-126-overexpressing osteosarcoma cells. In conclusion, DDP and MTX inhibited the proliferation and promoted the apoptosis of the osteosarcoma cells, and these processes were dependent upon the expression of miR-126.

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A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG

Flores

Kelly

et al. 2016

Cancer

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Background Osteosarcoma is the most common malignant pediatric bone tumor. Identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. In this study, we investigated the significance of circulating cytokines/chemokines to predict prognosis at initial diagnosis. Experimental design We employed Luminex assays to measure cytokine/chemokine concentrations from blood samples in a discovery cohort of osteosarcoma patients from Texas Children's Hospital (n= 37) and an independent validation cohort obtained from the Children's Oncology Group (n= 233). Following validation of biomarkers, we constructed a multivariable model to stratify patients into risk groups. Results The circulating concentrations of CXCL10, FLT3LG, IFNG, and CCL4 were significantly associated with overall survival in both cohorts. Of these candidates, CXCL10 and FLT3LG were independent from the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer-versus-control. By combining CXCL10, FLT3LG and metastatic status at diagnosis, we developed a multivariate model that significantly stratified the patients into four distinct risk groups (p = 1.6e-8). Survival analysis showed that 5-year overall survival rates for the “Low”, “Intermediate”, “High” and “Very-high” risk groups were 77%, 54%, 47%, and 10% respectively, while 5-event-free survival rates were 64%, 47%, 27%, and 0% respectively. Neither CXCL10 nor FLT3LG tumor expression were significantly associated with survival. Conclusions High circulating levels of CXCL10 and FLT3LG predicted worse survival in osteosarcoma. Since both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy in osteosarcoma.

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Impact of RANK signalling on survival and chemotherapy response in osteosarcoma

Cited by 38 publications

References 32 publications

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

Receptor activator of nuclear factor κB expression is a prognostic factor in human osteosarcoma

MicroRNA-126 enhances the sensitivity of osteosarcoma cells to cisplatin and methotrexate

A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG

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