Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue

Lau, Yu Sin; Sabokbar, A; Gibbons, C. L. M. H.; Giele, Henk; Athanasou, Nicholas A.

doi:10.1016/j.humpath.2005.07.005

Cited by 126 publications

(116 citation statements)

References 32 publications

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“…Our findings suggest that melanoma fibroblasts may induce osteoclast formation by a RANKL-dependent mechanism, and that this most likely occurs through the release of soluble RANKL. This feature has been reported in fibroblasts found in giant cell tumour of bone (Lau et al, 2005), a tumour that contains numerous osteoclasts, but not in normal fibroblast populations, including skin, bone marrow stromal cells, as well as fibroblasts derived from other non-neoplastic tissue (Quinn et al, 2000;Sabokbar et al, 2005;Sun et al, 2006). Stromal cells in primary melanoma are known to stimulate tumour progression and these cells may be activated in bone metastases to stimulate osteoclast differentiation and bone resorption (Spatz et al, 2002).…”

Section: Discussionmentioning

confidence: 92%

“…In order to determine if SK-Mel-29 CM has any effect on mature osteoclast activity, osteoclastic giant cells from two specimens of fresh giant cell tumour of bone were isolated by digestion with collagenase as previously described (Lau et al, 2005) and cultured in the presence and absence of SK-Mel-29 CM. Cultures on coverslips and dentine slices were maintained for 48 h.…”

Section: Sk-mel-29 Melanoma Cells: Effect On Mature Osteoclast Activitymentioning

confidence: 99%

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Malignant melanoma and bone resorption

et al. 2006

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The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14 þ /CD51À) differentiated into osteoclasts (CD14À/CD51 þ ) in the presence of receptor activator for nuclear factor kB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-a and interleukin (IL)-1a. RT -PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively.

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Section: Discussionmentioning

confidence: 92%

Section: Sk-mel-29 Melanoma Cells: Effect On Mature Osteoclast Activitymentioning

confidence: 99%

Malignant melanoma and bone resorption

et al. 2006

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“…Alternatively p63 could regulate cell death or proliferation. p63 can induce expression of molecules such as CD95 and TRAIL which influence apoptosis, [25][26][27][28] or inhibit proliferation by blocking binding of the NF-Y transcription factor which is required for transcription of cyclin B and cdk1 genes involved in regulating the cell cycle. 29 Determination of the functional significance of p63 in giant cell tumor of bone requires further study.…”

Section: Discussionmentioning

confidence: 99%

Giant cell tumor of bone express p63

Dickson

Wunder

et al. 2008

Modern Pathology

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p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear-or giant cellenriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (a, b, and c), whereas only low levels of the TAp63 a and b isoforms were detected in multinucleated cells; DNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.

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“…Multinucleated osteoclast-like giant cells (GC), actively resorbing host bone through cathepsin K activity [30], are variably mixed with a mononuclear cell component, among which proliferating spindle-shaped stromal cells (SC) with benign morphologic characteristics [24,28,37] and CD14 + -monocytes/CD68 + -macrophages are present [21,29]. Despite its benign histologic appearance, GCT has an unpredictable clinical course.…”

Section: Introductionmentioning

confidence: 99%

“…SC were therefore believed the most likely candidate neoplastic elements of GCT, partly based on their ability to grow both in vitro and in vivo [2,24]. SC exhibit markers of osteogenic differentiation [36,46] and are able to stimulate osteoclasts [34,37] through the ligand for receptor activator of nuclear factor kB (RANKL) [20,28,38], a growth factor essential for the recruitment of osteoclasts by osteoblasts under physiological conditions [18]. In agreement with a putative osteogenic origin of SC, osteoid foci may be found both inside and at the periphery of GCT [8,41], and bone formation, but no evidence of osteoclastogenesis has been observed in immunodeficient mice after subcutaneous injection of GCT tissue or cells [2,24].…”

Section: Introductionmentioning

confidence: 99%

Histogenetic Characterization of Giant Cell Tumor of Bone

Salerno

Avnet

Alberghini

et al. 2008

Clin Orthop Relat Res

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The unpredictable behavior of giant cell tumor (GCT) parallels its controversial histogenesis. Multinucleated giant cells, stromal cells, and CD68 + monocytes/ macrophages are the three elements that interact in GCT. We compared the ability of stromal cells and normal mesenchymal stromal cells to differentiate into osteoblasts. Stromal cells and mesenchymal cells had similar proliferation rates and lifespans. Although stromal cells expressed early osteogenic markers, they were unable to differentiate into osteoblasts but they did express intracellular adhesion molecule-1, a marker of bone-lining cells. They were unable to form clones in a semisolid medium and unable to promote osteoclast differentiation, although they exerted a strong chemotactic effect on osteoclast precursors. Stromal cells may be either immature proliferating osteogenic elements or specialized osteoblast-like cells that fail to show neoplastic features but can induce the differentiation of osteoclast precursors. They might be secondarily induced to proliferate by a paracrine effect induced by monocytemacrophages and/or giant cells. The increased number of giant cells in GCT may be secondary to an autocrine circuit mediated by the receptor activator of nuclear factor kB.

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Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue

Cited by 126 publications

References 32 publications

Malignant melanoma and bone resorption

Malignant melanoma and bone resorption

Giant cell tumor of bone express p63

Histogenetic Characterization of Giant Cell Tumor of Bone

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