Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis

Forsyth, Ramses; Krenács, Tibor; Athanasou, Nicholas A.; Hogendoorn, Pancras C.W.

doi:10.3390/cancers13205119

Cited by 15 publications

(11 citation statements)

References 131 publications

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“…GCTB is a locally aggressive and rarely metastasizing neoplasm histologically composed of a mononuclear cellular component (round histiocytes and elongated neoplastic cells) and osteoclastlike giant cells (14). It is still difficult to understand the cell biology of GCTB, that is the interaction of the different cell types, but a generally accepted concept has been described by Forsyth et al (15) recently: there is a crosstalk between m/wt nucleosome H3.3, telomeres and osteoclastogenesis. Extensive studies (16)(17)(18) revealed the mechanism of interaction between the macrophage and osteoclast-like cell populations, which express nuclear factor kappa B (RANK) and the stromal cells, which produce RANK ligand (RANKL).…”

Section: Discussionmentioning

confidence: 99%

The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases

Antal¹,

Pápai

Szabó³

et al. 2022

Pathol. Oncol. Res.

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Due to the relatively high recurrence rate and the destructive nature of the tumor, the treatment of giant cell tumor is still a challenge. Denosumab appeared to be a promising candidate as a therapeutic drug. However, several studies have reported that tumors can recur during/after treatment with denosumab. Based on activated receptor tyrosine kinase signaling pattern of the stromal/tumor cells, a combination treatment with denosumab and sunitinib has recently been proposed to inhibit recurrences. This prompted us to investigate the PDGFRβ expression of five denosumab treated cases using both primary and recurrent tumors during and after denosumab treatment. In addition, to recognise morphological changes, immunohistochemical analysis of H3F3A and PDGFRβ was also performed. As an effect of denosumab treatment, the permanent absence of giant cells associated with severe to mild fibrosis was the most consistent morphological change, but H3F3A positive stromal/tumor cells were observed in all cases. Furthermore, an increased immunopositivity of PDGFRβ in stromal/tumor cells was evident in all recurrent cases during denosumab treatment. Upon tumor recurrence (after the discontinuation of denosumab treatment) the intensity of PDGFRβ immunostaining in stromal/tumor cells was restored/decreased. Our results confirm (for the first time) the activation of PDGFRβ on mononuclear stromal/tumor cells at protein level as an effect of denosumab treatment, which has so far only been demonstrated by phosphoprotein array analysis (protein lysates). The decreased PDGFRβ activity after the discontinuation of denosumab treatmeant and the increased PDGFRβ activity during denosumab treatment underlines the need for denosumab and sunitinib combination therapy.

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Section: Discussionmentioning

confidence: 99%

The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases

Antal¹,

Pápai

Szabó³

et al. 2022

Pathol. Oncol. Res.

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“…Neoplastic stromal cells express RANKL, a surface marker, which has a pivotal role in the signaling pathway of bone remodeling and in the differentiation of precursors into giant multinucleated osteoclast-like cells, which can be considered activated components, influencing osteoclastogenesis and cell proliferation (tumorigenesis) [ 2 , 22 , 41 ]. RANKL overexpression in the tumoral stroma is associated to OPG negative feedback inhibition and decreased OPG gene expression, whose combination induces osteoclastic giant cell formation by the fusion of macrophagic precursors [ 41 , 45 ]. Furthermore, multinucleated giant cells, stromal cells and monocytic cells produce high levels of matrix metalloproteinase 14 (MMP14), which is responsible for the cleavage of membrane-bound RANKL into soluble RANKL, thus promoting osteoclastogenesis [ 45 , 46 ].…”

Section: Gctb Cytology Histopathogenesis and New Biomarkers In Molecular Targeted Therapy Eramentioning

confidence: 99%

“…RANKL overexpression in the tumoral stroma is associated to OPG negative feedback inhibition and decreased OPG gene expression, whose combination induces osteoclastic giant cell formation by the fusion of macrophagic precursors [ 41 , 45 ]. Furthermore, multinucleated giant cells, stromal cells and monocytic cells produce high levels of matrix metalloproteinase 14 (MMP14), which is responsible for the cleavage of membrane-bound RANKL into soluble RANKL, thus promoting osteoclastogenesis [ 45 , 46 ].…”

Section: Gctb Cytology Histopathogenesis and New Biomarkers In Molecular Targeted Therapy Eramentioning

confidence: 99%

State of the Art and New Concepts in Giant Cell Tumor of Bone: Imaging Features and Tumor Characteristics

Parmeggiani

Miceli

Errani

et al. 2021

Cancers

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Giant cell tumor of bone (GCTB) is classified as an intermediate malignant tumor due to its locally aggressive behavior, burdened by high local recurrence rate. GCTB accounts for about 4–5% of all primary bone tumors and typically arises in the metaphysis and epiphyses of the long tubular bones. Mutation of gene H3F3A is at the basis of GCTB etiopathogenesis, and its immunohistochemical expression is a valuable method for practical diagnosis, even if new biomarkers have been identified for early diagnosis and for potential tumor recurrence prediction. In the era of computer-aided diagnosis, imaging plays a key role in the assessment of GCTB for surgical planning, patients’ prognosis prediction and post treatment evaluation. Cystic changes, penetrating irregular margins and adjacent soft tissue invasion on preoperative Magnetic Resonance Imaging (MRI) have been associated with a higher rate of local recurrence. Distance from the tumor edge to the articular surface and thickness of unaffected cortical bone around the tumor should be evaluated on Computed Tomography (CT) as related to local recurrence. Main features associated with local recurrence after curettage are bone resorption around the graft or cement, soft tissue mass formation and expansile destruction of bone. A denosumab positive response is represented by a peripherical well-defined osteosclerosis around the lesion and intralesional ossification. Radiomics has proved to offer a valuable contribution in aiding GCTB pre-operative diagnosis through clinical-radiomics models based on CT scans and multiparametric MR imaging, possibly guiding the choice of a patient-tailored treatment. Moreover, radiomics models based on texture analysis demonstrated to be a promising alternative solution for the assessment of GCTB response to denosumab both on conventional radiography and CT since the quantitative variation of some radiomics features after therapy has been correlated with tumor response, suggesting they might facilitate disease monitoring during post-denosumab surveillance.

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“…Mechanisms related to TPE-OLD also have been reported recently based on a study of giant cell tumor of bone (GCTB), which is a rare bone tumor [ 92 ]. The authors suggested that the reactivation of h TERT transcription is related to the length of the telomeres, suggesting that TPE-OLD may be involved in the acquisition of telomerase reactivation during the development of GCTB.…”

Section: Telomere Position Effect-over Long Distances (Tpe-old)mentioning

confidence: 99%

Regulation of Gene Expression by Telomere Position Effect

Lee

Kim

2021

IJMS

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Many diseases that involve malignant tumors in the elderly affect the quality of human life; therefore, the relationship between aging and pathogenesis in geriatric diseases must be under-stood to develop appropriate treatments for these diseases. Recent reports have shown that epigenetic regulation caused by changes in the local chromatin structure plays an essential role in aging. This review provides an overview of the roles of telomere shortening on genomic structural changes during an age-dependent shift in gene expression. Telomere shortening is one of the most prominent events that is involved in cellular aging and it affects global gene expression through genome rearrangement. This review provides novel insights into the roles of telomere shortening in disease-affected cells during pathogenesis and suggests novel therapeutic approaches.

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Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis

Cited by 15 publications

References 131 publications

The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases

The Activation of PDGFRβ on Mononuclear Stromal/Tumor Cells in Giant Cell Tumor of Bone After Denosumab Treatment. An Immunohistochemical Study of Five Cases

State of the Art and New Concepts in Giant Cell Tumor of Bone: Imaging Features and Tumor Characteristics

Regulation of Gene Expression by Telomere Position Effect

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