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Collagenase expression and activity in the stromal cells from giant cell tumour of bone.

ABSTRACT: The characteristic bone destruction in giant cell tumour of bone (GCT) is largely attributed to the osteoclast-like giant cells. However, experimental analyses of bone resorption by cells from GCT often fail to exclude the neoplastic spindle-like stromal cells, and several studies have demonstrated that bone resorption by GCT cells is increased in the presence of stromal cells. The spindle-like stromal cells from GCT may therefore actively contribute to the bone resorption observed in the tumour. Type I collagen, a major organic constituent of bone, is effectively degraded by three matrix metalloproteinases (MMPs) known as the collagenases: MMP-1, MMP-8 and MMP-13. We established primary cell cultures from nine patients with GCT and the stromal cell populations were isolated in culture. The production of collagenases by primary cultures of GCT stromal cells was determined through real-time PCR, western blot analysis and a multiplex assay system. Results show that the cells produce MMP-1 and MMP-13 but not MMP-8. Immunohistochemistry confirmed the presence of MMP-1 and MMP-13 in paraffin-embedded GCT tissue samples. Medium conditioned by the stromal cell cultures was capable of proteolytic activity as determined by MMP-1 and MMP-13-specific standardized enzyme activity assays. The spindle-like stromal cells from GCT may therefore actively participate in the bone destruction that is characteristic of the tumour.

SUBMITTER: Cowan RW

PROVIDER: S-EPMC2894938 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Collagenase expression and activity in the stromal cells from giant cell tumour of bone.

Cowan Robert W RW Mak Isabella W Y IW Colterjohn Nigel N Singh Gurmit G Ghert Michelle M

Bone 20090212 5

The characteristic bone destruction in giant cell tumour of bone (GCT) is largely attributed to the osteoclast-like giant cells. However, experimental analyses of bone resorption by cells from GCT often fail to exclude the neoplastic spindle-like stromal cells, and several studies have demonstrated that bone resorption by GCT cells is increased in the presence of stromal cells. The spindle-like stromal cells from GCT may therefore actively contribute to the bone resorption observed in the tumour ...[more]

PMID: 19442604

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Project description:The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Dataset Information

Collagenase expression and activity in the stromal cells from giant cell tumour of bone.

Publications

Collagenase expression and activity in the stromal cells from giant cell tumour of bone.

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