Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene, with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene, CDK4 amplification, and allelic loss of the RB gene, as well as for expression of p16 and pRb proteins. Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells. Thus, p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb, and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations, none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two low-grade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas.
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PMID:CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. 966 76

High-grade osteosarcoma is characterized by extensive genetic instability, thereby hampering the identification of causative gene mutations and understanding of the underlying pathological processes. It lacks a benign precursor lesion and reports on associations with hereditary predisposition or germline mutations are uncommon, despite the early age of onset. Here we demonstrate a novel comprehensive approach for the study of premalignant stages of osteosarcoma development in a murine mesenchymal stem cell (MSC) system that formed osteosarcomas upon grafting. By parallel functional and phenotypic analysis of normal MSCs, transformed MSCs and derived osteosarcoma cells, we provide substantial evidence for a MSC origin of osteosarcoma. In a stepwise approach, using COBRA-FISH karyotyping and array CGH in different passages of MSCs, we identified aneuploidization, translocations and homozygous loss of the cdkn2 region as the key mediators of MSC malignant transformation. We then identified CDKN2A/p16 protein expression in 88 osteosarcoma patients as a sensitive prognostic marker, thereby bridging the murine MSCs model to human osteosarcoma. Moreover, occasional reports in patients mention osteosarcoma formation following bone marrow transplantation for an unrelated malignancy. Our findings suggest a possible hazard for the clinical use of MSCs; however, they also offer new opportunities to study early genetic events in osteosarcoma genesis and, more importantly, to modulate these events and record the effect on tumour progression. This could be instrumental for the identification of novel therapeutic strategies, since the success of the current therapies has reached a plateau phase.
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PMID:Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. 1971 9

Usage of cancer cell lines has repeatedly generated conflicting results provoked by differences among subclones or contamination with mycoplasm or other immortal mammalian cells. To overcome these limitations, we decided within the EuroBoNeT consortium to characterize a common set of cell lines including osteosarcomas (OS), Ewing sarcomas (ES), and chondrosarcomas (CS). DNA fingerprinting was used to guarantee the identity of all of the cell lines and to distinguish subclones of osteosarcoma cell line HOS. Screening for homozygous loss of 38 tumor suppressor genes by MLPA revealed deletion of CDKN2A as the most common event (15/36), strictly associated with absence of the CDKN2A (p16) protein. Ten cell lines showed missense mutations of the TP53 gene while another set of nine cell lines showed mutations resulting in truncation of the TP53 protein. Cells harboring missense mutations expressed high levels of nuclear TP53, while cell lines with nonsense mutations showed weak/absent staining for TP53. TP53(wt) cell lines usually expressed the protein in 2-10% of the cells. However, seven TP53(wt) osteosarcomas were negative for both mRNA and protein expression. Our analyses shed light on the correlation between immunohistochemical and genetic data for CDKN2A and TP53, and confirm the importance of these signaling pathways. The characterization of a substantial number of cell lines represents an important step to supply research groups with proven models for further advanced studies on tumor biology and may help to make results from different laboratories more comparable.
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PMID:Molecular characterization of commonly used cell lines for bone tumor research: a trans-European EuroBoNet effort. 1978 92

MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including the cell cycle regulator E2F2. MIR31 and CDKN2A, which encode p14(ARF) and p16(INK4A), are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14(ARF) promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14(ARF) to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14(ARF)-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially affecting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31.
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PMID:Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers. 2017 98

Conventional osteosarcoma is characterized by rapid growth, high local aggressiveness, and metastasizing potential. Patients developing lung metastases experience poor prognosis despite extensive chemotherapy regimens and surgical interventions. Previously we identified a subgroup of osteosarcoma patients with loss of CDKN2A/p16 protein expression in the primary tumor biopsies which was significantly predictive of a very poor prognosis. Here we aimed to identify the underlying mechanism(s) of this protein loss in relation to osteosarcoma behavior. The CDKN2A locus was analyzed in osteosarcoma cases with total loss of CDKN2A/p16 expression and in cases with high protein expression using melting curve analysis-methylation assay (MCA-Meth), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and mutation analysis. All cases with complete CDKN2A/p16 protein loss showed homozygous deletions at the CDKN2A locus. In none of the cases hyper methylation of the promoter region was seen which was confirmed by sequencing this region. Taken together we show that large or smaller deletions of the CDKN2A locus are evident in patient samples and underlie the CDKN2A/p16 protein expression loss while promoter methylation does not appear to be a mechanism of this expression loss. Genomic loss of CDKN2A instead of promoter methylation might be a plausible explanation for the rapid proliferation and high aggressiveness of osteosarcoma by simultaneous impairment CDKN2A/p14(ARF) function.
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PMID:Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma. 2073 80

Controlling cell fate-determining gene expression is key to stem cell differentiation, tissue regeneration, and cancer therapy. To date, custom-built transcription factors recognize the information encoded in specific DNA sequences. Chromatin proteins undergo covalent modifications and form complexes that encode a second layer of information that determines proximal gene activity. Here, we employ a novel gene-targeting approach that exploits a specific chromatin modification to reactivate silenced loci in human cells. We used the human Polycomb chromatin protein and homologues from other species to construct modular synthetic transcription factors, called Pc-TFs, that recognize the repressive trimethyl-histone H3 lysine 27 (H3K27me3) signal and switch silenced genes to an active state. Pc-TF expression in U2OS osteosarcoma cells leads to increased transcription of the senescence locus CDKN2A (p16) and other loci in a chromodomain- and activation module-dependent manner, a switch to a senescence phenotype, and reduced cell proliferation. These results indicate that silenced developmental regulators can be reactivated by a synthetic transcription factor that interacts with chromatin rather than DNA, resulting in an altered cell state. As such, our work extends the flexibility of transcription factor engineering and is the first example of chromatin-mediated synthetic transcription factor targeting.
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PMID:Synthetic reversal of epigenetic silencing. 2166 65

Molecular cytogenetic evaluation of human osteosarcoma (OS) has revealed the characteristically high degree of genomic reorganization that is the hallmark of this cancer. The extent of genomic disorder in OS has hindered identification of the genomic aberrations driving disease progression. With pathophysiological similarities to its human counterpart, canine OS represents an ideal model for comparison of conserved regions of genomic instability that may be disease-associated rather than genomic passengers. This study used high-resolution oligonucleotide array comparative genomic hybridization and a variety of informatics tools to aid in the identification of disease-associated genome-wide DNA copy number aberrations in canine and human OS. Our findings support and build upon the high level of cytogenetic complexity, through the identification of shared regions of microaberration (<500 kb) and functional analysis of possible orthologous OS-associated genes to pinpoint the cellular processes most commonly affected by aberration in human and canine OS. Aberrant regions contained previously reported genes such as CDC5L, MYC, RUNX2, and CDKN2A/CDKN2B, while expanding the gene of interest list to include ADAM15, CTC1, MEN1, CDK7, and others. Such regions of instability may thus have functional significance in the etiology of OS, the most common primary bone tumor in both species.
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PMID:A genome-wide approach to comparative oncology: high-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations. 2313 72

Chondrosarcomas are cartilage-forming, poorly vascularized tumors. They represent the second malignant primary bone tumor of adults after osteosarcoma, but in contrast to osteosarcoma they are resistant to chemotherapy and radiotherapy, surgical excision remaining the only therapeutic option. Few cell lines and animal models are available, and the mechanisms behind their chemoresistance remain largely unknown. Our goal was to establish new cell lines and animal cancer models from human chondrosarcoma biopsies to study their chemoresistance. Between 2007 and 2012, 10 chondrosarcoma biopsies were collected and used for cell culture and transplantation into nude mice. Only one transplanted biopsy and one injected cell line has engrafted successfully leading to conventional central high-grade chondrosarcoma similar to the original biopsies. In culture, two new stable cell lines were obtained, one from a dedifferentiated and one from a grade III conventional central chondrosarcoma biopsy. Their genetic characterization revealed triploid karyotypes, mutations in IDH1, IDH2, and TP53, deletion in CDKN2A and/or MDM2 amplification. These cell lines expressed mesenchymal membrane markers (CD44, 73, 90, 105) and were able to produce a hyaline cartilaginous matrix when cultured in chondrogenic three-dimensional (3D) pellets. Using a high-throughput quantitative RT-PCR approach, we observed that cell lines cultured in monolayer had lost expression of several genes implicated in cartilage development (COL2A1, COMP, ACAN) but restored their expression in 3D cultures. Chondrosarcoma cells in monolayer were sensitive to several conventional chemotherapeutic agents but became resistant to low doses of mafosfamide or doxorubicin when cultured in 3D pellets, in parallel with an altered nucleic accumulation of the drug. Our results indicate that the cartilaginous matrix produced by chondrosarcoma cells may impair diffusion of several drugs and thus contribute to chemoresistance. Therefore, 3D chondrogenic cell pellets constitute a more relevant model to study chondrosarcoma chemoresistance and may be a valuable alternative to animal experimentations.
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PMID:New chondrosarcoma cell lines and mouse models to study the link between chondrogenesis and chemoresistance. 2395 80

Sixty years ago, 6-thioguanine (6-TG) was introduced into the clinic. We suggest its full potential in therapy may not have been reached. In this paper, we contrast 6-TG and the more widely used 6-mercaptopurine; discuss 6-TG metabolism, pharmacokinetics, dosage and schedule; and summarize many of the early studies that have shown infrequent but nevertheless positive results with 6-TG treatment of cancers. We also consider studies that suggest that combinations of 6-TG with other agents may enhance antitumor effects. Although not yet tested in man, 6-TG has recently been proposed to treat a wide variety of cancers with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP), often codeleted with the adjacent tumor suppressor CDKN2A (p16). Among the cancers with a high frequency of MTAP deficiency are leukemias, lymphomas, mesothelioma, melanoma, biliary tract cancer, glioblastoma, osteosarcoma, soft tissue sarcoma, neuroendocrine tumors, and lung, pancreatic, and squamous cell carcinomas. The method involves pretreatment with the naturally occurring nucleoside methylthioadenosine (MTA), the substrate for the enzyme MTAP. MTA pretreatment protects normal host tissues, but not MTAP-deficient cancers, from 6-TG toxicity and permits administration of doses of 6-TG that are much higher than can now be safely administered. The combination of MTA/6-TG has produced substantial shrinkage or slowing of growth in two different xenograft human tumor models: lymphoblastic leukemia and metastatic prostate carcinoma with neuroendocrine features. Further development and a clinical trial of the proposed MTA/6-TG treatment of MTAP-deficient cancers seem warranted.
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PMID:6-thioguanine: a drug with unrealized potential for cancer therapy. 2492 12

Osteosarcoma (OS), a bone tumor, exhibit a complex karyotype. On the genomic level a highly variable degree of alterations in nearly all chromosomal regions and between individual tumors is observable. This hampers the identification of common drivers in OS biology. To identify the common molecular mechanisms involved in the maintenance of OS, we follow the hypothesis that all the copy number-associated differences between the patients are intercepted on the level of the functional modules. The implementation is based on a network approach utilizing copy number associated genes in OS, paired expression data and protein interaction data. The resulting functional modules of tightly connected genes were interpreted regarding their biological functions in OS and their potential prognostic significance. We identified an osteosarcoma network assembling well-known and lesser-known candidates. The derived network shows a significant connectivity and modularity suggesting that the genes affected by the heterogeneous genetic alterations share the same biological context. The network modules participate in several critical aspects of cancer biology like DNA damage response, cell growth, and cell motility which is in line with the hypothesis of specifically deregulated but functional modules in cancer. Further, we could deduce genes with possible prognostic significance in OS for further investigation (e.g. EZR, CDKN2A, MAP3K5). Several of those module genes were located on chromosome 6q. The given systems biological approach provides evidence that heterogeneity on the genomic and expression level is ordered by the biological system on the level of the functional modules. Different genomic aberrations are pointing to the same cellular network vicinity to form vital, but already neoplastically altered, functional modules maintaining OS. This observation, exemplarily now shown for OS, has been under discussion already for a longer time, but often in a hypothetical manner, and can here be exemplified for OS.
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PMID:Genomic heterogeneity of osteosarcoma - shift from single candidates to functional modules. 2584 66


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