West, R. B. et al. A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc. Natl Acad. Sci. USA 103, 690-695

Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2006; 103(3):690-5. DOI: 10.1073/pnas.0507321103
Source: PubMed


Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.

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    • "Dt-GCT patients, chromosomal translocations involving the gene encoding CSF-1 result in overexpression of this cytokine by cells within the synovial lining (West et al., 2006). This leads to massive recruitment of CSF-1R-expressing cells, mainly nonmalignant mononuclear and multinucleated cells that form the bulk tumorous mass (Cupp et al., 2007; West et al., 2006). Marginal excision or complete synovectomy remain the treatments of choice (Ravi et al., 2011) for Dt-GCT, but the disorder sometimes necessitates mutilating surgery due to locally destructive and recurring tumor growth. "
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    ABSTRACT: Macrophage infiltration has been identified as an independent poor prognostic factor in several cancer types. The major survival factor for these macrophages is macrophage colony-stimulating factor 1 (CSF-1). We generated a monoclonal antibody (RG7155) that inhibits CSF-1 receptor (CSF-1R) activation. In vitro RG7155 treatment results in cell death of CSF-1-differentiated macrophages. In animal models, CSF-1R inhibition strongly reduces F4/80(+) tumor-associated macrophages accompanied by an increase of the CD8(+)/CD4(+) T cell ratio. Administration of RG7155 to patients led to striking reductions of CSF-1R(+)CD163(+) macrophages in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor (Dt-GCT) patients.
    Cancer Cell 05/2014; DOI:10.1016/j.ccr.2014.05.016 · 23.52 Impact Factor
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    • "Chromosome 2 was the translocation partner in a subset (3 of 10) of tumors and collagen type VI α-3 (COL6A3) was then identified as the partner gene involved at 2q37. Moreover, combined interphase FISH and CSF1 immunohistochemistry demonstrated that only a minority (2–16%) of the cells in the tumor samples carried the t(1;2)(p13;q37) and that only those cells expressed CSF1, while tissue microarray analyses showed that the CSF1 receptor gene CSF1R is highly overexpressed in TSGCT (20). To explain these findings, it was suggested that the translocation involving CSF1 and COL6A3 results in a high level of CSF1 expression in the neoplastic parenchyma cells, which in turn recruit also non-neoplastic CSF1R-expressing cells. "
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    ABSTRACT: RNA-sequencing was performed on three tenosynovial giant cell tumors (TSGCT) in an attempt to elicit more information on the mechanisms of CSF1 expression in this tumor type. A novel CSF1-S100A10 fusion gene was found in a TSGCT that carried the translocation t(1;1)(q21;p11) as the sole karyotypic abnormality. In this fusion gene, the part of CSF1 coding for the CSF1 protein (exons 1-8 in sequences with accession nos. NM_000757 and NM_172212) is fused to the 3'-part of S100A10. Since the stop codon TAG of CSF1 is present in it, the CSF1-S100A10 fusion gene's predominant consequence seems to be the replacement of the 3'-untranslated region (UTR) of CSF1 (exon 9; nt 2092-4234 in sequence with accession no. NM_000757 or nt 2092-2772 in NM_172212) by the 3'-end of S100A10 (exon 3; nt 641-1055 in sequence with accession no. NM_002966). In the other two TSGCT, a novel CSF1 transcript was detected, the same in both tumors. Similar to the occurrence in the CSF1-S100A10 fusion gene, the novel CSF1 transcript 3'-UTR is replaced by a new exon located ~48 kb downstream of CSF1 and 11 kb upstream of AHCYL1. Although only 3 TSGCT were available for study, the finding in all of them of a novel CSF1-S100A10 fusion gene or CSF1 transcript indicates the existence of a common pathogenetic theme in this tumor type: the replacement of the 3'-UTR of CSF1 with other sequences.
    International Journal of Oncology 03/2014; 44(5). DOI:10.3892/ijo.2014.2326 · 3.03 Impact Factor
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    • "CSF1R ligand, is overexpressed in PVNS due to a specific t(1;2) translocation, which fuses the CSF1 gene to the collagen type VI a3 (COL6A3) promoter. CSF1, in turn, attracts non-neoplastic inflammatory cells expressing the CSF1 receptor (CSF1R) through a paracrine effect [4]. CSF1 is an inflammatory mediator which is present together with its receptor (CSF1R) in human synovia. "
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    ABSTRACT: Background Pigmented villonodular synovitis (PVNS) is a rare locally aggressive tumor. PVNS is characterized in most cases by a specific t(1;2) translocation, which fuses the colony stimulating factor-1 (CSF1) gene to the collagen type VIa3 (COL6A3) promoter thus leading through a paracrine effect to the attraction of non-neoplastic inflammatory cells expressing CSF1-receptor. Imatinib is a tirosin-kinase inhibitors (TKI) active against CSF1-receptor whose activity in naïve PVNS was already described. We report on two PVNS patients who responded to imatinib after failure to nilotinib, another CSF1-receptor inhibitor. Methods Since August 2012, 2 patients with progressive, locally advanced PVNS resistant to nilotinib (Patient 1: man, 34 years; Patient 2: woman, 24 years) have been treated with second-line imatinib 400 mg/day. Both patients are evaluable for response. Results Both patients are still on treatment (7 and 4 months). Patient 1 had a dimensional response by MRI after 2 months from starting imatinib, together with symptomatic improvement. In Patient 2 a metabolic response was detected by [18F]fluorodeoxyglucose–positron emission tomography (PET) at 6 weeks coupled with tumor shrinkage by MRI, and symptomatic improvement. Conclusions Imatinib showed antitumor activity in 2 patients with nilotinib-resistant PVNS. This observation strengthen the idea that targeted agent with similar profile can give a different clinical result, as already described for gastrointestinal stromal tumor (GIST) patients treated with the same agents. Molecular studies are needed to clarify the biologic mechanism(s) underlying the response.
    05/2013; 3(1):8. DOI:10.1186/2045-3329-3-8
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