Knock-down of oncohistone H3F3A-G34W counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells

Background The giant cell tumor (GCT) is a benign tumor which consists of three types cells: mononuclear histiocytic cells (MNHCs), multinuclear giant cells (MNGCs), and GCT stromal cells (GCTSCs). Numerous studies claim that GCTSCs have mesenchymal stem cells (MSCs) characters and play an important role in osteoclastogenesis; however, there are no research studies concerning macrophage polarization among GCT, which can be regarded as an ingredient for tumor aggression. Method We tested the effect of GCTSCs from three GCT samples which were collected from patients on proliferation, apoptosis and polarization of macrophage. Result In this article, we verified that GCTSCs expressed MSCs markers and had higher proliferation and relative lower differentiation abilities compared with BMMSCs. What’s more, we found a higher proportion of M2 macrophages among neoplasm. Co-culturing GCTSCs with macrophages resulted in prominent macrophage M2 polarization and increased the release of IL-6 (Interleukin-6) and IL-10 (Interleukin-10)from GCTSCs. In conclusion, GCTSCs, as originating from MSCs, can secret IL-6 and IL-10, which may play a significant role in macrophage M2 polarization.

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Histomorphometric Analysis of Pre- and Post-Denosumab–Treated Giant Cell Tumor of Bone

International Journal of Surgical Pathology ◽

10.1177/1066896920920716 ◽

2020 ◽

Vol 28 (8) ◽

pp. 859-867

Author(s):

Nasir Ud Din ◽

Masood Umer ◽

Yong-Koo Park

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Mononuclear Cells ◽

Giant Cells ◽

Cell Tumor ◽

P Value ◽

Osteoblastic Activity ◽

Woven Bone ◽

Hematoxylin And Eosin

Context. Denosumab is a monoclonal antibody against RANK ligand. Its administration in giant cell tumor of bone (GCTB) cases results in elimination of giant cells and new bone formation. Neoplastic stromal cells of GCTB harbor mutation of histone 3.3 and have pre-osteoblastic properties and thus express SATB2. Objectives. To (1) analyze histological changes in post-denosumab–treated GCTB, (2) analyze expression of H3.3G34W and SATB2 in pre- and post-denosumab–treated samples, and (3) to discuss why changes occur in the expression of not only H3.3G34W but also SATB2. Materials and Methods. Hematoxylin and eosin slides of 19 cases of denosumab-treated GCTB were reviewed. Immunohistochemical stains H3.3G34W and SATB2 were performed. The number of positive mononuclear cells were counted and graded. Results. Complete absence of osteoclast-like giant cells (OCLGCs) was noted in most cases along with a fibro-osseous component merging with peripheral shell of reactive bone. Irregular trabeculae of woven bone and osteoid with focal osteoblastic rimming was seen. Spindle cells were arranged predominantly in fascicular pattern. Morphometric analysis of H3.3G34W showed a mean of 68.8% positive stromal cells in pretreatment and a mean of 26.9% positive stromal cells in posttreated specimens with a statistically significant P value (.001). Mean percentage of SATB2-positive stromal cells in the pre- and posttreatment specimens was 36.46% and 20.8%, respectively. Conclusions. Our study validates that denosumab treatment results in marked reduction of OCLGCs with increased osteoblastic activity. Decreased expression of H3.3G34W in posttreatment may be a result of decreased antigenicity of neoplastic mononuclear cells. No significant change in SATB2 expression was noted.

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Simvastatin Possesses Antitumor and Differentiation‐Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone

Journal of Orthopaedic Research® ◽

10.1002/jor.24456 ◽

2019 ◽

Vol 38 (2) ◽

pp. 297-310 ◽

Cited By ~ 4

Author(s):

Carol P. Y. Lau ◽

Cathy S. H. Fung ◽

Kwok Chuen Wong ◽

Yu‐Hsuan Wang ◽

Lin Huang ◽

...

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Cell Tumor

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A microRNA signature differentiates between giant cell tumor derived neoplastic stromal cells and mesenchymal stem cells

Cancer Letters ◽

10.1016/j.canlet.2012.01.043 ◽

2012 ◽

Vol 321 (2) ◽

pp. 162-168 ◽

Cited By ~ 19

Author(s):

Joerg Fellenberg ◽

Heiner Saehr ◽

Burkhard Lehner ◽

Daniela Depeweg

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Cell Tumor

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Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone

Nature Communications ◽

10.1038/s41467-020-18955-y ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Pavlo Lutsik ◽

Annika Baude ◽

Daniela Mancarella ◽

Simin Öz ◽

Alexander Kühn ◽

...

Keyword(s):

Dna Methylation ◽

Osteogenic Differentiation ◽

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Chromatin Accessibility ◽

Cell Tumor ◽

Epigenetic Alterations ◽

Epigenetic Landscape ◽

Line System

Abstract The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.

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The Role of TWIST in Angiogenesis and Cell Migration in Giant Cell Tumor of Bone

Advances in Biology ◽

10.1155/2014/903259 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Shalini Singh ◽

Isabella W. Y. Mak ◽

Divya Handa ◽

Michelle Ghert

Keyword(s):

Cell Migration ◽

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Epithelial Mesenchymal Transition ◽

Cell Tumor ◽

Stable Cell Line ◽

Mesenchymal Transition

Giant cell tumor of bone (GCT) is a bone tumor consisting of numerous multinucleated osteoclastic giant cells involved in bone resorption and neoplastic osteoblast-like stromal cells responsible for tumor growth. The tumor occasionally metastasizes to the lung; however, factors leading to metastasis in this tumor are unknown. The TWIST-1 protein (also referred to as TWIST) has been suggested to be involved in epithelial-mesenchymal transition (EMT) and tumor progression in some cancers. In this study we investigated the functional role of TWIST in GCT cell angiogenesis and migration. Overexpression of TWIST in neoplastic GCT stromal cells significantly increased mRNA and protein expression of VEGF and VEGFR1 in vitro, whereas knockdown of TWIST resulted in decreased VEGF and VEGFR1 expression. A stable cell line with TWIST overexpression resulted in features of EMT including increased cell migration and downregulation of E-cadherin. The results of our study indicate that TWIST may play an important role in angiogenesis and cell migration in GCT.

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