Multiple osteochondromas

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and it seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15–18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities, especially of the forearm, that may be reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5–5%. MO is an autosomal dominant disorder and is genetically heterogeneous. In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization. The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of osteochondromas. If the exact mutation is known antenatal diagnosis is technically possible. MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease. Osteochondromas are benign lesions and do not affect life expectancy. Management includes removal of osteochondromas when they give complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed

Bone: Enchondroma

Review on Enchondroma, with data on clinics, and the genes involved

Bone: Osteochondroma

Review on Osteochondroma, with data on clinics, and the genes involved

Bone: Conventional Osteosarcoma

Review on Osteosarcoma, with data on clinics, and the genes involved

Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management

Multiple Osteochondromas is an autosomal dominant disorder characterised by the presence of multiple osteochondromas and a variety of orthopaedic deformities. Two genes causative of Multiple Osteochondromas, Exostosin-1 (EXT1) and Exostosin-2 (EXT2), have been identified, which act as tumour suppressor genes. Osteochondroma can progress towards its malignant counterpart, secondary peripheral chondrosarcoma and therefore adequate follow-up of Multiple Osteochondroma patients is important in order to detect malignant transformation early

Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>We investigated the protein expression of estrogen receptor alpha (ESR1), androgen receptor (AR), and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary) chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4) or exemestane (n = 2) treatment in 6 chondrosarcoma patients with progressive disease was explored.</p> <p>Results</p> <p>We showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma <it>in vitro</it>. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients.</p> <p>Conclusions</p> <p>The presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our <it>in vitro </it>and pilot <it>in vivo </it>studies have shown no effect of estrogen-signaling inhibition on tumor growth.</p

Kinome profiling of myxoid liposarcoma reveals NF-kappaB-pathway kinase activity and Casein Kinase II inhibition as a potential treatment option

<p>Abstract</p> <p>Background</p> <p>Myxoid liposarcoma is a relatively common malignant soft tissue tumor, characterized by a (12;16) translocation resulting in a FUS-DDIT3 fusion gene playing a pivotal role in its tumorigenesis. Treatment options in patients with inoperable or metastatic myxoid liposarcoma are relatively poor though being developed and new hope is growing.</p> <p>Results</p> <p>Using kinome profiling and subsequent pathway analysis in two cell lines and four primary cultures of myxoid liposarcomas, all of which demonstrated a FUS-DDIT3 fusion gene including one new fusion type, we aimed at identifying new molecular targets for systemic treatment. Protein phosphorylation by activated kinases was verified by Western Blot and cell viability was measured before and after treatment of the myxoid liposarcoma cells with kinase inhibitors. We found kinases associated with the atypical nuclear factor-kappaB and Src pathways to be the most active in myxoid liposarcoma. Inhibition of Src by the small molecule tyrosine kinase inhibitor dasatinib showed only a mild effect on cell viability of myxoid liposarcoma cells. In contrast, inhibition of the nuclear factor-kappaB pathway, which is regulated by the FUS-DDIT3 fusion product, in myxoid liposarcoma cells using casein kinase 2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) showed a significant decrease in cell viability, decreased phosphorylation of nuclear factor-kappaB pathway proteins, and caspase 3 mediated apoptosis. Combination of dasatinib and TBB showed an enhanced effect.</p> <p>Conclusion</p> <p>Kinases associated with activation of the atypical nuclear factor-kappaB and the Src pathways are the most active in myxoid liposarcoma <it>in vitro </it>and inhibition of nuclear factor-kappaB pathway activation by inhibiting casein kinase 2 using TBB, of which the effect is enhanced by Src inhibition using dasatinib, offers new potential therapeutic strategies for myxoid liposarcoma patients with advanced disease.</p

BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

BACKGROUND: As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. METHODS: Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. RESULTS: The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. CONCLUSIONS: The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells

Reclassification and subtyping of so-called malignant fibrous histiocytoma of bone: comparison with cytogenetic features

<p>Abstract</p> <p>Background</p> <p>The diagnostic entity malignant fibrous histiocytoma (MFH) of bone is, like its soft tissue counterpart, likely to be a misnomer, encompassing a variety of poorly differentiated sarcomas. When reviewing a series of 57 so-called MFH of bone within the framework of the EuroBoNeT consortium according to up-to-date criteria and ancillary immunohistochemistry, a fourth of all tumors were reclassified and subtyped.</p> <p>Methods</p> <p>In the present study, the cytogenetic data on 11 of these tumors (three myoepithelioma-like sarcomas, two leiomyosarcomas, one undifferentiated pleomorphic sarcoma with incomplete myogenic differentiation, two undifferentiated pleomorphic sarcomas, one osteosarcoma, one spindle cell sarcoma, and one unclassifiable biphasic sarcoma) are presented.</p> <p>Results</p> <p>All tumors were high-grade lesions and showed very complex karyotypes. Neither the overall pattern (ploidy level, degree of complexity) nor specific cytogenetic features distinguished any of the subtypes. The subgroup of myoepithelioma-like sarcomas was further investigated with regard to the status of the <it>EWSR1 </it>and <it>FUS </it>loci; however, no rearrangement was found. Nor was any particular aberration that could differentiate any of the subtypes from osteosarcomas detected.</p> <p>Conclusions</p> <p>chromosome banding analysis is unlikely to reveal potential genotype-phenotype correlations between morphologic subtypes among so-called MFH of bone.</p

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone

BackgroundChondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce.MethodsWe developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential.ResultsWe show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5–8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type.ConclusionsBased on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies