Stromal Cell-Derived CCL20 Promotes Tumor Progression and Osteolysis in Giant Cell Tumor of Bone

Background/Aims: Giant cell tumor of bone (GCTB), one of the most common primary bone tumors, leads to extensive bone destruction. However, the mechanisms underlying GCTB progression remain elusive and prognostic factors and treatment targets are required. In the current study, we explored the function of the chemokine family member CCL20 in GCTB progression. Methods: We explored the expression of CCL20 in stromal cells (GCTSCs) using microarray. Clinical analyses of the role of CCL20 in tumor progression were performed based on the patient cohort of our institution. The role of CCL20 in tumor proliferation was evaluated by MTS assay, migration ability was measured by a Transwell assay, and osteoclastogenesis was induced by CCL20 or GCTSC-conditioned medium. Quantitative PCR and western blot were used to measure the expression levels of mRNAs and proteins related to tumor progression. Results: CCL20 was upregulated in GCTSCs and correlated with tumor progression and prognosis. CCL20 induced GCTSC proliferation and migration in an autocrine manner. In addition, CCL20 recruited mononuclear cells and induced osteoclastogenesis by overactivating the AKT and NF-κB signaling pathways. Antibody blockade of CCL20 abolished the exacerbated osteoclastogenesis. Conclusion: Taken together, our data indicate that GCTSC secretion of CCL20 acts as a key modulator in the pathological progression of GCTB. It can promote GCTSC proliferation and migration in an autocrine manner and can recruit bone marrow monocytes to the tumor microenvironment and enhance osteoclastogenesis in a paracrine manner. These findings strongly indicate the potential prognostic and therapeutic value of CCL20 in GCTB.

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Denosumab in the Treatment of Giant Cell Tumor of Bone

Oncology & Hematology Review (US) ◽

10.17925/ohr.2010.06.0.39 ◽

2010 ◽

Vol 06 ◽

pp. 39

Author(s):

David Thomas ◽

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Population ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Osteoclast Formation ◽

Cell Tumor ◽

Rare Benign Tumor ◽

And Function

Giant cell tumor of bone (GCT) is a rare, benign tumor characterized by localized bone destruction. GCT is thought to be biphenotypic, comprising a neoplastic stromal cell population and an osteoclast-like giant cell population. Recent studies have established that receptor activator of NF κβ ligand (RANKL) plays an important role in GCT. Although its actions are not fully understood, RANKL acts as an obligate signal for normal osteoclast formation and function. The development of an antagonist to RANKL, denosumab, has led to clinical trials in osteoporosis, bone metastases in cancer, and GCT. Generally well-tolerated, denosumab is an extremely effective inhibitor of osteoclast differentiation and function in humans. A preliminary study of the use of denosumab in patients with advanced or unresectable GCT has suggested considerable activity and clinical benefit. The eventual role of denosumab in GCT is currently the subject of an ongoing clinical trial.

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Role of radiologic imaging in management planning of giant cell tumor of bone

Skeletal Radiology ◽

10.1007/bf00360811 ◽

1984 ◽

Vol 12 (2) ◽

pp. 79-89 ◽

Cited By ~ 27

Author(s):

E. Levine ◽

A. A. De Smet ◽

J. R. Neff

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Tumor ◽

Management Planning ◽

Radiologic Imaging

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RECURRENCE OF GIANT CELL TUMOR OF BONE: THE ROLE OF MRI IN DIAGNOSIS

Orthopedics ◽

10.3928/0147-7447-19970101-14 ◽

1997 ◽

Vol 20 (1) ◽

pp. 67-69

Author(s):

Barry J Waldman ◽

Elias A Zerhouni ◽

Frank J Frassica

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Tumor

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Giant Cell Poor Extra-Articular Diffuse-Type Tenosynovial Giant Cell Tumor With Extensive Desmin Expression: A Potential Diagnostic Pitfall With Cytogenetic Confirmation

International Journal of Surgical Pathology ◽

10.1177/1066896918788678 ◽

2018 ◽

Vol 27 (1) ◽

pp. 59-61

Author(s):

Liurka Lopez ◽

Karen Schoedel ◽

Ivy John

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Mononuclear Cells ◽

Giant Cells ◽

Cell Tumor ◽

Diffuse Type ◽

Tenosynovial Giant Cell Tumor ◽

Diagnostic Pitfall

Diffuse-type tenosynovial giant cell tumor can rarely present as an entirely extra-articular mass, which can be misdiagnosed as a sarcoma especially when giant cells are absent, dominated by large dendritic mononuclear cells, and desmin expression is extensive.

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Calcitonin receptors on neoplastic mononuclear cells cultured from a human giant-cell tumor of the sacrum

Journal of Cancer Research and Clinical Oncology ◽

10.1007/bf01236383 ◽

1994 ◽

Vol 120 (5) ◽

pp. 272-278 ◽

Cited By ~ 5

Author(s):

Akio Maeda ◽

Hisao Matsui ◽

Masahiko Kanamori ◽

Kazuo Yudoh ◽

Haruo Tsuji

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Mononuclear Cells ◽

Cell Tumor ◽

Calcitonin Receptors ◽

Cells Cultured

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Role of Bisphosphonates as Adjuvants of Surgery in Giant Cell Tumor of Spine

The International Journal of Spine Surgery ◽

10.14444/5087 ◽

2018 ◽

Vol 12 (6) ◽

pp. 695-702

Author(s):

CHAITANYA DEV PANNU ◽

PANKAJ KANDHWAL ◽

VIJAY RAGHAVAN ◽

SHAH ALAM KHAN ◽

SHISHIR RASTOGI ◽

...

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Tumor

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Giant Cell Tumor of Tendon Sheath: Immunohistochemical Study of 20 Cases

Tumori Journal ◽

10.1177/030089169708300514 ◽

1997 ◽

Vol 83 (5) ◽

pp. 841-846 ◽

Cited By ~ 10

Author(s):

Antonio Cavaliere ◽

Angelo Sidoni ◽

Emilio Bucciarelli

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Mononuclear Cells ◽

Neuron Specific Enolase ◽

Synovial Cell ◽

Tendon Sheath ◽

Giant Cells ◽

Cell Tumor ◽

Electron Microscopic ◽

Filament Bundles

Aims and background Giant cell tumor of tendon sheath (GCTTS) is a common tumor occurring on the tendon sheaths of the fingers. The nature of this lesion is still controversial: some researchers consider it a reactive process arising from chronic inflammation while others regard it as a tumor of presumed synovial cell or monocytic macrophage system origin. In an effort to clarify the histogenesis we decided to further investigate the immunophenotypic profile of this tumor. Study design We studied 20 GCTTS of the fingers using a panel of 18 antibodies, 13 monoclonal and 5 polyclonal. Results The immunohistochemical investigation revealed that the mononuclear cells of this lesion can be divided into two groups. The cells of the first and more numerous group were positive for vimentin, PG-M1 and KP1 but also for muscle actin (HHF35 monoclonal antibody) and neuron-specific enolase. A second population of mononuclear cells, usually arranged around the giant cells, were positive for PG-M1, KP1, LCA and occasionally for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Multinucleated giant cells were also positive for KP1, PG-M1 and LCA monoclonal antibodies. A variable but usually weak positivity for al-pha-1-antitrypsin, alpha-1-antichymotrypsin and lysozyme was also observed. Conclusions Our results suggest a synovial cell origin for GCTTS and do not support the hypothesis that it could be a neoplasm with a true histiocytic origin. The positivity of some cells for the HHF35 antibody, together with electron microscopic evidence of filament bundles with focal dense bodies, suggests that at least part of the mononuclear cells may have a myofibroblastic differentiation.

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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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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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