Ewing sarcoma cells express RANKL and support osteoclastogenesis

Taylor, Rhiannon; Knowles, Helen J.; Athanasou, Nicholas A.

doi:10.1002/path.2869

Cited by 37 publications

(26 citation statements)

References 44 publications

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“…The initial clinical symptoms of ES may include pain, intermittent fever, anemia, increased white blood cell counts, high C-reactive protein concentration, and sedimentation rate, which are the symptoms of systemic inflammatory reactions [1, 8]. ES tumors are also associated with necrosis and rapid, extensive osteolysis [9, 10]. Osteoclast formation in ES is mediated by RANKL-dependent pathway and promoted by the tumor-associated macrophages (TAMs) [8, 9, 11].…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications

et al. 2014

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Ewing sarcoma (ES) is a group of highly aggressive small round cell tumors of bone or soft tissue with high metastatic potential and low cure rate. ES tumors are associated with a rapid osteolysis and necrosis. The currently accepted clinical prognostic parameters do not accurately predict survival of high-risk patients. Moreover, neither the subtype of EWS–FLI1/ERG in the tumor, nor the detection of fusion transcripts in the peripheral blood (PB) samples, has prognostic value in ES patients. We evaluated the prevalence of circulating tumor cells (CTCs) in 34 adult ES patients. Since CTCs were confirmed in only small subset of patients, we further explored the expression profiles of PB leukocytes using a panel of genes associated with immune system status and increased tumor invasiveness. Moreover, we analyzed the alterations of the routine blood tests in the examined cohort of patients and correlated our findings with the clinical outcome. A uniform decrease in ZAP70 expression in PB cells among all ES patients, as compared to healthy individuals, was observed. Monocytosis and the abnormal expression of CDH2 and CDT2 genes in the PB cells significantly correlated with poor prognosis in ES patients. Our study supports the previously proposed hypothesis of systemic nature of ES. Based on the PB cell expression profiles, we propose a mechanism by which immune system may be involved in intensification of osteoclastogenesis and disease progression in ES patients. Moreover, we demonstrate the prognostic value of molecular PB testing at the time of routine histopathological diagnosis.

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications

et al. 2014

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“…This is in contrast to the work of Taylor et al, who identified RANK-ligand expression and MCSF expression in ESB tumor cells and tumor needle biopsy samples. (20) Recent work by Fujiwara et al has identified TRAP-positive tumor-associated-macrophages (TAM) located near subcutaneously implanted Ewing's tumor in a Balb/c mouse model. (14) Further, these investigators identified that MCSF and RANK-ligand gene expression were observed in several Ewing's sarcoma tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone

Margulies

DeBoyace

Damron

et al. 2015

Bone

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Ewing's sarcoma of bone is a primary childhood malignancy of bone that is treated with X-radiation therapy in combination with surgical excision and chemotherapy. To better study Ewing's sarcoma of bone we developed a novel model of primary Ewing's sarcoma of bone and then treated animals with X-radiation therapy. We identified that uncontrolled tumor resulted in lytic bone destruction while X-radiation therapy decreased lytic bone destruction and increased limb-length asymmetry, a common, crippling complication of X-radiation therapy. Osteoclasts were indentified adjacent to the tumor, however, we were unable to detect RANK-ligand in the Ewing's tumor cells in vitro, which lead us to investigate alternate mechanisms for osteoclast formation. Ewing's sarcoma tumor cells and archival Ewing's sarcoma of bone tumor biopsy samples were shown to express MCSF, which could promote osteoclast formation. Increased monocyte numbers were detected in peripheral blood and spleen in animals with untreated Ewing's sarcoma tumor while monocyte number in animals treated with x-radiation had normal numbers of monocytes. Our data suggest that our Ewing's sarcoma of bone model will be useful in the study Ewing's sarcoma tumor progression in parallel with the effects of chemotherapy and X-radiation therapy.

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“…High expression of factors responsible for osteoclastogenesis (RANKL, M-CSF) by osteosarcoma cell lines MG63 and Saos-2 was demonstrated in in vitro experiments [5,6], and a clinical study has demonstrated a significant relationship between high RANKL expression in the tumor and a poor response of osteosarcoma patients to neoadjuvant chemotherapy: high RANKL expression levels were associated with low 5-years' overall survival [7]. Increased expression of RANK/RANKL/OPG system components was also found in chondrosarcoma [8], Ewing sarcoma [9], and some bone tissue benign tumor-like lesions [10].…”

Section: Introductionmentioning

confidence: 96%

Receptor Activator of Nuclear Transcription Factor Nf-b (Rank), Its Ligand (Rankl) and Natural Inhibitor Osteoprotegerin (Opg) in Blood Serum of Primary Bone Tumor Patients: Association With Clinicopathological Features and Inflammatory Cytokines Levels

Kushlinskii¹,

Es²,

Timofeev³

et al. 2017

RAD Conference Proceedings

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Abstract. RANK/RANKL/OPG system (the key regulator of bone homeostasis) component levels were measured in blood serum of 199 patients with primary bone tumors and tumor-like lesions: 121 with bone sarcomas (53 osteosarcoma, 46 chondrosarcoma, 12 chordoma, 8 Ewing sarcoma), 32 with borderline giant cell bone tumor (GCBT), 46 with benign bone neoplasms; 131 persons comprised the control group. OPG, sRANKL, sRANK, IL-6, 8, 16 serum levels were measured by standard ELISA kits. Giant-cell bone tumor (GCBT) manifesting high osteoclastogenic and osteolytic activities was characterized by high serum content of all three components studied and the highest sRANKL/OPG ratio. The group of patients with various benign bone tumors and tumor-like lesions displayed similar to GCBT, but lower indices. Malignant bone tumor patients could be divided into 2 subgroups with opposite characteristics: osteosarcoma and Ewing sarcoma patients demonstrated low sRANK and high sRANKL levels, while chondrosarcoma and chordoma patients, on the contrary -high sRANK and low sRANKL levels. The highest IL-6 levels were revealed in GCBT patients, while serum IL-8 and IL-16 did not differ between groups. Thus, disturbances in osteolysis activators and inhibitors balance in blood serum of primary bone tumor patients were revealed. Their extent depended on neoplasm character (malignant, borderline, or benign) and histological structure of malignant sarcomas. Most prominent changes were found in GCBT characterized by active bone destruction and an accepted target of anti-RANKL antibody denosumab treatment. Hence, the proteins studied can be regarded as promising serologic markers and therapeutic targets in this rare disease.

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Ewing sarcoma cells express RANKL and support osteoclastogenesis

Cited by 37 publications

References 44 publications

Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications

Gene expression profiling of peripheral blood cells: new insights into Ewing sarcoma biology and clinical applications

Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone

Receptor Activator of Nuclear Transcription Factor Nf-b (Rank), Its Ligand (Rankl) and Natural Inhibitor Osteoprotegerin (Opg) in Blood Serum of Primary Bone Tumor Patients: Association With Clinicopathological Features and Inflammatory Cytokines Levels

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