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Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-?/SMAD3 autocrine loop.

ABSTRACT: Abnormal stem cell function makes a known contribution to many malignant tumors, but the role of stem cells in benign tumors is not well understood. Here, we show that ossifying fibroma (OF) contains a stem cell population that resembles mesenchymal stem cells (OFMSCs) and is capable of generating OF-like tumor xenografts. Mechanistically, OFMSCs show enhanced TGF-? signaling that induces aberrant proliferation and deficient osteogenesis via Notch and BMP signaling pathways, respectively. The elevated TGF-? activity is tightly regulated by JHDM1D-mediated epigenetic regulation of thrombospondin-1 (TSP1), forming a JHDM1D/TSP1/TGF-?/SMAD3 autocrine loop. Inhibition of TGF-? signaling in OFMSCs can rescue their abnormal osteogenic differentiation and elevated proliferation rate. Furthermore, chronic activation of TGF-? can convert normal MSCs into OF-like MSCs via establishment of this JHDM1D/TSP1/TGF-?/SMAD3 autocrine loop. These results reveal that epigenetic regulation of TGF-? signaling in MSCs governs the benign tumor phenotype in OF and highlight TGF-? signaling as a candidate therapeutic target.

SUBMITTER: Qin H

PROVIDER: S-EPMC3861239 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop.

Qin Haiyan H Qu Cunye C Yamaza Takayoshi T Yang Ruili R Lin Xia X Duan Xue-Yan XY Akiyama Kentaro K Liu Yi Y Zhang Qunzhou Q Chen Chider C Chen Yibu Y Qi Hank Heng HH Feng Xin-Hua XH Le Anh D AD Shi Songtao S

Cell stem cell 20131101 5

Abnormal stem cell function makes a known contribution to many malignant tumors, but the role of stem cells in benign tumors is not well understood. Here, we show that ossifying fibroma (OF) contains a stem cell population that resembles mesenchymal stem cells (OFMSCs) and is capable of generating OF-like tumor xenografts. Mechanistically, OFMSCs show enhanced TGF-β signaling that induces aberrant proliferation and deficient osteogenesis via Notch and BMP signaling pathways, respectively. The el ...[more]

PMID: 24209761

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Project description:BackgroundTricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture.Case presentationA 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared.ConclusionsIn conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis.

Dataset Information

Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-?/SMAD3 autocrine loop.

Publications

Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop.

Similar Datasets

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