Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone

Balla, Péter; Moskovszky, Linda; Szepes, Zoltán; Forsyth, Ramses; Knowles, Helen J.; Athanasou, Nick; Szabó, Miklós; Kopper, László; Rajnai, Hajnalka; Pintér, Ferenc; Peták, I.; Benassi, Maria Serena; Picci, Piero; Conti, Amalia; Krenács, Tibor

doi:10.1111/j.1365-2559.2011.03948.x

Cited by 22 publications

(12 citation statements)

References 49 publications

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“…The cells were counted using a hemocytometer and resuspended at a density of 5x10 5 cells/20 µl PBS. For morphological observation and TRAP staining, 1x10 5 cells were seeded in 6-well plate and cultured in DMEM supplemented with 10% FBS, 100 U/ml penicillin and 100 µg/ml streptomycin in a 37˚C humidified incubator with 5% CO 2 (30).…”

Section: Patient-derived Gctb Cells Collection and Cells Culturementioning

confidence: 99%

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

Zhou

et al. 2018

Oncol Lett

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There have been various reports in the literature of an model for giant cell tumor of bone (GCTB). However, few suitable animal models of GCTB have been established, due to the fact that GCTB contains three histologically different cell types. To the best of our knowledge, injection of patient-derived GCTB cells into bone environment has not been reported until now. In the present study, the biological behavior of GCTB cells in nude mice was investigated through intratibial injection of patient-derived GCTB cells. Patient-derived GCTB cells were obtained from 5 patients who had not undergone chemo- and radiotherapy. Once isolated, the cell suspension was injected into the tibias of nude mice. The growth process was monitored by weekly observation and photographic documentation using X-ray. Four months after injection, nude mice were sacrificed and the injected tibial samples were fixed, and further analyzed using micro-computed tomography (micro-CT), standard histology, tartrate-resistant acid phosphatase (TRAP) staining and mitochondrial immunofluorescence staining. X-ray, micro-CT and standard histology revealed osteolytic destruction in the proximal end of the tibia. TRAP staining identified TRAP-positive, osteoclast-like cells distributed in the bone marrow interface of the lesion area. Anti-human mitochondrial immunofluorescence staining confirmed that the surviving cells in the osteolytic destruction were of human GCTB cell origin. These findings indicate that intratibial injection of patient-derived GCTB cells may elicit osteolytic destruction in nude mice. The results of the current study present a novel animal model for GCTB, opening new perspectives to investigate this disease and develop therapeutic agents.

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Section: Patient-derived Gctb Cells Collection and Cells Culturementioning

confidence: 99%

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

Zhou

et al. 2018

Oncol Lett

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“…CD33 1 , which is characteristic for GCTB, may constitute a novel therapeutic target, analogous to the treatment of acute myeloid leukemia with gemtuzumab, an anti-CD33 antibody [44]. Epidermal growth factor receptor (EGFR) signaling, a tyrosine kinase expressed by neoplastic mononuclear stromal cells, supports stromal cell proliferation and promotes osteoclastogenesis in the presence of M-CSF [46]. EGFR expression was more frequent in recurrent and metastatic disease, suggesting that it may be related to disease progression [46].…”

Section: Histopathologymentioning

confidence: 99%

The Clinical Approach Toward Giant Cell Tumor of Bone

et al. 2014

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We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor kB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intraarticular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTBderived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable. The Oncologist 2014;19:550-561 Implications for Practice: Giant cell tumor of bone (GCTB) is an intermediate, locally aggressive, primary bone tumor. Ideally, all patients should be treated with intralesional excision with local adjuvant treatment (e.g., phenol, liquid nitrogen, polymethylmethacrylate), achieving joint salvage and optimal functional outcome. In patients with high-risk GCTB or in rare cases of metastatic disease, systemic targeted therapy with the receptor activator of nuclear factor kB ligand inhibitor denosumab is highly effective and may create an operable situation. Moderate-dose radiotherapy is indicated only for rare cases of unresectable, residual or recurrent GCTB in which denosumab is contraindicated or unavailable for preoperative treatment and when surgery would lead to unacceptable morbidity.

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“…In addition, two other targets frequently found expressed in GCT tumor tissues are the glycoprotein of the extracellular matrix tenascin C (TNC) and the Epidermal Growth Factor Receptor (EGFR), described associated with GCT tumor progression. However, even less is known about the biochemical alteration in pagetic GCT [ 19 – 20 ]. From a genetic point of view, we identified the responsible mutation (p.Pro937Arg) in patients with GCT/PDB in the ZNF687 gene that encodes a component of the Z3 complex involved in interpreting the histone code for chromatin remodelling for transcription [ 21 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

The distinct clinical features of giant cell tumor of bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences

et al. 2017

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Giant Cell Tumor of Bone (GCT) is a tumor characterized by neoplastic mesenchymal stromal cells and a high number of osteoclast-like multinucleated giant cells. Rarely, GCT could arise in bones affected by Paget's disease of bone (GCT/PDB). Although it is already known that GCT/PDB and GCT show a different clinical profile regarding the age-onset and skeletal localization, our deep clinical comparison between the two GCT/PDB and GCT cohorts, permitted us to identify additional differences (e.g. focality, ALP serum levels, the 5-year survival rate and the familial recurrence), strongly suggesting a different molecular basis. Accordingly, driver somatic mutations in H3F3A and IDH2 were described in GCT patients, while we recently identified a germline mutation in ZNF687 as the genetic defect of GCT/PDB patients.Here, we detected H3F3A mutations in our GCT cohort, confirming its molecular screening as the elected diagnostic tool, and then we excluded the two-hit in H3F3A and IDH2 as the trigger event for the GCT/PDB development. Importantly, we also identified an alternative biochemical profile with GCT/PDB not exhibiting the up-regulation of the GCT marker FGFR2IIIc. Finally, our histological analysis also showed a different appearance of the two forms of the tumor, with GCT/PDB showing a higher number of osteoclast-like giant cells (twice), with an abnormal number of nuclei per cell, corroborating its different behaviour in terms of neoplastic properties.We demonstrated that the distinct clinical features of pagetic and conventional GCT are associated with different genetic background, resulting in a specific biochemical and histological behaviour of the tumour.

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Epidermal growth factor receptor signalling contributes to osteoblastic stromal cell proliferation, osteoclastogenesis and disease progression in giant cell tumour of bone

Abstract: In GCTB, EGFR signalling in neoplastic stromal cells may contribute to disease progression through promoting stromal cell proliferation and osteoclastogenesis.

Cited by 22 publications

References 49 publications

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

Intratibial injection of patient‑derived tumor cells from giant cell tumor of bone elicits osteolytic reaction in nude mouse

The Clinical Approach Toward Giant Cell Tumor of Bone

The distinct clinical features of giant cell tumor of bone in pagetic and non-pagetic patients are associated with genetic, biochemical and histological differences

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