Expression of Osteoclast Differentiation Signals by Stromal Elements of Giant Cell Tumors

Atkins, Gerald J.; Haynes, David R.; Graves, Stephen E.; Evdokiou, Andreas; Hay, Shelley; Bouralexis, Stelios; Findlay, David M.

doi:10.1359/jbmr.2000.15.4.640

Cited by 175 publications

(81 citation statements)

References 31 publications

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“…28 Expression of osteoclastogenic factors by GCTB mononuclear cells is in keeping with the hypothesis that these cells express growth factors promoting osteoclast formation. 20,29 VEGF-A and RANKL expression by GCTB giant cells and M-CSF expression in enriched cultures of GCTB giant cells has been reported in previous studies. 30 Previous work has shown that M-CSF can inhibit or stimulate osteoclast resorption activity depending on the resorption model and species of osteoclast employed.…”

Section: Osteoclastogenesis By M-csf Substitutes Rm Taylor Et Almentioning

confidence: 52%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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Giant cell tumour of bone (GCTB) is a primary bone tumour that contains numerous very large, hyper-nucleated osteoclastic giant cells. Osteoclasts form from CD14 þ monocytes and macrophages in the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). GCTB contains numerous growth factors, some of which have been reported to influence osteoclastogenesis and resorption. We investigated whether these growth factors are capable of substituting for M-CSF to support osteoclast formation from cultured human monocytes and whether they influence osteoclast cytomorphology and resorption. Vascular endothelial growth factor-A (VEGF-A), VEGF-D, FLT3 ligand (FL), placental growth factor (PlGF) and hepatocyte growth factor (HGF) supported RANKL-induced osteoclastogenesis in the absence of M-CSF, resulting in the formation of numerous TRAP þ multinucleated cells capable of lacunar resorption. Monocytes cultured in the presence of M-CSF, HGF, VEGF-A and RANKL together resulted in the formation of very large, hyper-nucleated (GCTB-like) osteoclasts that were hyper-resorptive. M-CSF and M-CSF substitute growth factors were identified immunohistochemically in GCTB tissue sections and these factors stimulated the resorption of osteoclasts derived from a subset of GCTBs. Our findings indicate that there are growth factors that are capable of substituting for M-CSF to induce human osteoclast formation and that these factors are present in GCTB where they influence osteoclast cytomorphology and have a role in osteoclast formation and resorption activity. The osteoclast is a multinucleated cell, which is formed from circulating mononuclear phagocyte precursors derived from the bone marrow. 1,2 It exhibits a number of specialised cytochemical and functional features, including the ability to carry out lacunar bone resorption. Increased osteoclast formation and activity is seen in a number of osteolytic bone and joint conditions, including notably giant cell tumour of bone (GCTB), a primary bone tumour, which contains numerous, very large, often hyper-nucleated osteoclastic giant cells that effect a considerable amount of bone resorption. 3,4 Osteoclast differentiation from monocyte or macrophage precursors requires the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). 5 The importance of M-CSF in osteoclast formation is evidenced by the fact that in op/op osteopetrotic mice, which have a mutation in the M-CSF gene, very few osteoclasts are found in bone and there is markedly decreased bone resorption. 6,7 M-CSF promotes several aspects of osteoclastogenesis including the proliferation and fusion of osteoclast precursors as well as osteoclasts and the expression of the RANKL receptor by these cells. [8][9][10] The effect of M-CSF on mature osteoclast resorption activity is controversial with both a decrease and increase in lacunar resorption being reported. [11][12][13] Although bone resorption is gre...

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Section: Osteoclastogenesis By M-csf Substitutes Rm Taylor Et Almentioning

confidence: 52%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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“…GCTB contains 3 histologically different cell types: round to oval polygonal or elongated mononuclear stromal tumor cells, a minor component of reactive rounded mononuclear cells of monocyte lineage representing precursors of the giant cells, and evenly scattered giant cells. In many publications, the mononuclear stromal cells are reported to overexpress RANKL and are thought to be the true neoplastic components of GCTB (2,7,10,13). These transformed mononuclear stromal cells have been shown to express many characteristics of mesenchymal stem cells that have differentiated along the osteoblast lineage but not to a completely differentiated osteoblast phenotype, with minimal expression of such factors as osteocalcin and alkaline phosphatase (14-17, 26, 27).…”

Section: Discussionmentioning

confidence: 99%

“…Histologically, GCTB is composed of sheets of neoplastic ovoid mononuclear cells with high RANK ligand (RANKL) expression, RANK-positive mononuclear cells of myeloid linage, and a randomly distributed population of large RANKexpressing osteoclast-like giant cells (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Many researchers have shown that the giant cell of GCTB is osteoclastic in nature (4,6,10) and that the true neoplastic cells are ovoid cells displaying markers of mesenchymal stem cells that have partially differentiated along the osteoblast lineage (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

Branstetter

Nelson

Manivel

et al. 2012

Clinical Cancer Research

378

301

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Purpose: Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB.Experimental Design: Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL.Results: Baseline tumor samples were typically composed of densely cellular proliferative RANKLpositive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells.Conclusions: Denosumab treatment of patients with GCTB significantly reduced or eliminated RANKpositive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.

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“…OPG, RANKL and/or RANK expression are dysregulated in a number of cancers in bone, including osteoclastoma [135] and PCa [136]. RANKL expression was identified in the epithelium and stroma of clinical PCa specimens [136] and increasing levels correlate with increased stage of disease [137] suggesting that it can serve as a prognostic factor [138] [142,143].…”

Section: Receptor Activator Of Nfkb Ligandmentioning

confidence: 99%

The PCa Tumor Microenvironment

Sottnik

Zhang

Macoska

et al. 2011

Cancer Microenvironment

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The tumor microenvironment (TME) is a very complex niche that consists of multiple cell types, supportive matrix and soluble factors. Cells in the TME consist of both host cells that are present at tumor site at the onset of tumor growth and cells that are recruited in either response to tumor-or host-derived factors. PCa (PCa) thrives on crosstalk between tumor cells and the TME. Crosstalk results in an orchestrated evolution of both the tumor and microenvironment as the tumor progresses. The TME reacts to PCa-produced soluble factors as well as direct interaction with PCa cells. In return, the TME produces soluble factors, structural support and direct contact interactions that influence the establishment and progression of PCa. In this review, we focus on the host side of the equation to provide a foundation for understanding how different aspects of the TME contribute to PCa progression. We discuss immune effector cells, specialized niches, such as the vascular and bone marrow, and several key protein factors that mediate host effects on PCa. This discussion highlights the concept that the TME offers a potentially very fertile target for PCa therapy.

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Expression of Osteoclast Differentiation Signals by Stromal Elements of Giant Cell Tumors

Cited by 175 publications

References 31 publications

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Denosumab Induces Tumor Reduction and Bone Formation in Patients with Giant-Cell Tumor of Bone

The PCa Tumor Microenvironment

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