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)

Seven samples from seven patients with juxtacortical osteosarcomas, and 27 samples from 19 patients with conventional high-grade osteosarcomas were investigated for a possible correlation between telomerase activity and clinicopathological features such as age, sex, and response to chemotherapy. Of seven juxtacortical osteosarcomas, telomerase activity was weakly positive in three parosteal osteosarcomas, and highly positive in one parosteal osteosarcoma. In contrast, of 27 conventional high-grade osteosarcomas, telomerase activity was weakly positive in eight tumors and highly positive in three. Of all samples, 44.1% of the osteosarcomas showed telomerase activity (57.1% of juxtacortical and 40.7% of conventional osteosarcomas). The majority of poor responders to chemotherapy showed no telomerase activity (nine of 11), whereas five of seven good responders showed strong or weak telomerase activity. There was a significant correlation between telomerase activity and the response to chemotherapy (P<0.05). Telomerase activity was not correlated with MIB-1 proliferation index, age at the time of surgery, or sex. These findings suggest that telomerase activation occurs early in the oncogenesis of osteoblastic tumors without having an effect on the progression of these tumors. In malignant osteoblastic tumors, the biological significance of telomerase activation is different from that described for most epithelial cancers.
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PMID:Telomerase activity in juxtacortical and conventional high-grade osteosarcomas: correlation with grade, proliferative activity and clinical response to chemotherapy. 1286 Feb 97

Overexpression of the retroviral oncoprotein v-Rel can rapidly transform and immortalize a variety of avian cells in culture. However, mammalian models for v-Rel-mediated oncogenesis have been compromised by the fact that high-level expression of v-Rel has been reported to be toxic in many mammalian cell types, including mouse 3T3 cells, Rat-1 cells, and mouse bone marrow cells. In this article, we demonstrate that 3T3 cells can support expression of v-Rel for at least 24 days when infected with a mouse stem cell virus (MSCV) retroviral vector containing v-rel. In retrovirus-infected 3T3 cells, v-Rel is located in the nucleus and can bind to DNA, but does not transform the cells. On the other hand, 3T3 and Rat-2 cells do not express v-Rel after stable transfection with a pcDNA-based v-Rel expression vector. We also show that infection of the IL3-dependent mouse B cell line BaF3 with the MSCV-v-rel vector results in expression of v-Rel, but does not convert these cells to growth factor independence. In contrast to 3T3 cells, the dog osteosarcoma D17 cell line can support a high level of v-Rel expression, after either transfection or infection with a retroviral vector. That is, v-Rel can be stably expressed as a nuclear, DNA-binding protein in D17 cells to approximately the same level as in chicken embryo fibroblasts. These results suggest that the restriction to v-Rel expression in rodent fibroblasts is generally absent in D17 cells and that the type of v-rel expression vector determines whether 3T3 cells can support stable expression of v-Rel. The findings reported here are an essential first step in the development of mammalian systems to study Rel-mediated oncogenesis.
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PMID:Stable expression of the avian retroviral oncoprotein v-Rel in avian, mouse, and dog cell lines. 1459 86

Transgenic mice overexpressing the c-Fos oncoprotein develop osteosarcomas that are associated with deregulated expression of cell cycle genes. Here we have generated osteoblast cell lines expressing c-fos under the control of a tetracycline-regulatable promoter to investigate the role of c-Fos in osteoblast cell cycle control in vitro. Three stable subclones, AT9.2, AT9.3, and AT9.7, derived from MC3T3-E1 mouse osteoblasts, expressed high levels of exogenous c-fos mRNA and protein in the absence of tetracycline. Functional contribution of ectopic c-Fos to AP-1 complexes was confirmed by electromobility shift assays and transactivation of AP-1 reporter constructs. Induction of exogenous c-Fos in quiescent AT9.2 cells caused accelerated S-phase entry following serum stimulation, resulting in enhanced growth rate. Ectopic c-Fos resulted in increased expression of cyclins A and E protein levels, and premature activation of cyclin A-, cyclin E-, and cyclin-dependent kinase (CDK) 2-associated kinase activities, although cyclin D levels and CDK4 activity were not affected significantly in these cell lines. The enhanced CDK2 kinase activity was associated with a rapid, concomitant dissociation of p27 from CDK2-containing complexes. Deregulated cyclin A expression and CDK2 activity was also observed in primary mouse osteoblasts overexpressing c-Fos, but not in fibroblasts, and c-Fos transgenic tumor-derived osteosarcoma cells constitutively expressed high levels of cyclin A protein. These data suggest that overexpression of c-Fos in osteoblasts results in accelerated S phase entry as a result of deregulated cyclin A/E-CDK2 activity. This represents a novel role for c-Fos in osteoblast growth control and may provide c-Fos-overexpressing osteoblasts with a growth advantage during tumorigenesis.
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PMID:Accelerated cell cycle progression in osteoblasts overexpressing the c-fos proto-oncogene: induction of cyclin A and enhanced CDK2 activity. 1469 50

The core protein of Hepatitis C virus affects several biological functions of the host cells such as cellular growth and apoptosis. The core was shown to interact with 53BP2/Bbp/ASPP2, a p53-binding protein, in a yeast two-hybrid assay. The core competed with p53 in binding to ASPP2 in vitro. In an apoptosis assay using human osteosarcoma Saos-2 cells or hepatocellular carcinoma HepG2 cells, ectopic expression of p53 induced apoptosis and ASPP2 enhanced this p53-induced apoptosis. However, coexpression of the core with p53 and ASPP2 increased the number of surviving cells. In a reporter assay, neither ASPP2 nor the core with ASPP2 affected the transcriptional activity of p53 on the promoters of Bax and p21, major p53 target genes. These findings suggest that the core inhibits p53-mediated apoptosis by blocking the interaction between p53 and ASPP2, without modulating the transcriptional activity of p53, which plays a role in oncogenesis of hepatocellular carcinoma.
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PMID:Hepatitis C virus core protein interacts with p53-binding protein, 53BP2/Bbp/ASPP2, and inhibits p53-mediated apoptosis. 1498 81

Methylation of promoter regions of CpG-rich sites is an important mechanism for silencing of tumor suppressor genes (TSG). To evaluate the role of tumor suppressor genes caspase-8 (CASP8), TIMP-3, E-cadherin (CDH1), p16INK4A, and MGMT in medulloblastoma tumorigenesis, 51 medulloblastomas (46 primary tumor specimens, 5 cell lines) were screened for methylation of promoter linked CpG-islands. For CASP8, we examined the 5' UTR region that has been shown to be associated with expression of CASP8. As detected by methylation specific PCR, methylation rate was low for TIMP-3 (3% of tumor samples; 1/5 cell lines), for MGMT (0% of tumor samples; 1/5 cell lines), for p16INK4A (2% of tumor samples; 2/5 cell lines) and for CDH1 (8% of tumor samples; 1/4 cell lines). CASP8, however, was methylated in 90% of tumor samples and 4/5 cell lines examined. Screening other tumor entities for CASP8 methylation, we found a similarly high level in 6 neuroblastoma cell lines in contrast to 5 osteosarcoma-, 4 Ewing's sarcoma- and 6 non-embryonic tumor cell lines without any increased promoter methylation. From our results we conclude that methylation of the CASP8 5' UTR region may play a role in inactivation of CASP8 in neural crest tumors.
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PMID:Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin in medulloblastoma. 1502 56

Tumorigenesis is associated with enhanced cellular glucose uptake and increased metabolism. Because the p53 tumor suppressor is mutated in a large number of cancers, we evaluated whether p53 regulates expression of the GLUT1 and GLUT4 glucose transporter genes. Transient cotransfection of osteosarcoma-derived SaOS-2 cells, rhabdomyosarcoma-derived RD cells, and C2C12 myotubes with GLUT1-P-Luc or GLUT4-P-Luc promoter-reporter constructs and wild-type p53 expression vectors dose dependently decreased both GLUT1 and GLUT4 promoter activity to approximately 50% of their basal levels. PG(13)-Luc activity, which was used as a positive control for functional p53 expression, was increased up to approximately 250-fold by coexpression of wild-type p53. The inhibitory effect of wild-type p53 was greatly reduced or abolished when cells were transfected with p53 with mutations in amino acids 143, 248, or 273. A region spanning -66/+163 bp of the GLUT4 promoter was both necessary and sufficient to mediate the inhibitory effects of p53. Furthermore, in vitro translated p53 protein was found to bind directly to two sequences in that region. p53-DNA binding was completely abolished by excess unlabeled probe but not by nonspecific DNA and was super-shifted by the addition of an anti-p53 antibody. Taken together, our data strongly suggest that wild-type p53 represses GLUT1 and GLUT4 gene transcription in a tissue-specific manner. Mutations within the DNA-binding domain of p53, which are usually associated with malignancy, were found to impair the repressive effect of p53 on transcriptional activity of the GLUT1 and GLUT4 gene promoters, thereby resulting in increased glucose metabolism and cell energy supply. This, in turn, would be predicted to facilitate tumor growth.
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PMID:The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. 1505 20

To further define the role of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in osteosarcoma (OS), human OS cell lines with low (SAOS-2) and high (SAOS-LM2) metastatic potential and three canine OS-derived cell lines were studied. Cell lines were evaluated for: IGF-1R expression; expression of IGF binding proteins (IGFBPs); effect of IGF-1 on tumor cell growth, invasion, expression of urokinase plasminogen activator (uPA), and soluble uPA receptor (suPAR), and; ectopic and orthotopic tumorigenicity of the canine OS cells in athymic mice. All cell lines exhibited steady-state mRNA expression of IGF-1R. The SAOS-2 and SAOS-LM2 cells expressed 9,138 and 10,234 cell-associated binding sites, respectively. Canine OS cells expressed from 1,728 to 3,883 binding sites. Two IGF-1-treated cell lines displayed enhanced proliferation. Two cell lines formed colonies in semisolid media, and IGF-1 increased colony number. Matrigel invasion was enhanced in one cell line following IGF-1 treatment. uPA and suPAR were unchanged in SAOS-2 and SAOS-LM2 cells following IGF-1 treatment, but the highly metastatic OS line SAOS-LM2 expressed five times more suPAR and displayed enhanced invasion compared to the parental, low metastatic SAOS-2. IGFBP-5 was detected in four of five cell lines, and IGFBP-3 was detected in two canine OS cell lines. Two canine OS lines were tumorigenic, and one metastasized spontaneously. In conclusion, OS cells express IGF-1R, which can contribute to their growth and invasion. There is suggestive evidence that increasing receptor number may contribute to in vivo tumorigenesis. Additional studies are needed to determine how IGF-1/IGF-1R interactions contribute to the malignant phenotype of OS.
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PMID:IGF-1 receptor contributes to the malignant phenotype in human and canine osteosarcoma. 1509 5

Osteosarcomas are malignant tumors of the bone that are characterized by complex genetic changes, including loss and amplification of chromosome regions. Region 17p11.2 approximately p12 is frequently found to be amplified in this tumor, suggesting the presence of an oncogene (or oncogenes) important in osteosarcoma tumorigenesis. We had previously determined amplification profiles for this region. Reasoning that amplification of a causative oncogene in a tumor should result in increased expression of that gene, we have now determined the expression status of genes and expressed sequence tags (ESTs) in 17p11.2 approximately p12. We constructed a 17p11.2 approximately p12-specific macroarray containing 40 genes and 21 ESTs from this region, which was used for expression profiling of 11 osteosarcoma samples (9 tumors and 2 cell lines) and of normal human osteoblasts. Compared to normal osteoblasts, genes with at least threefold increased expression were considered to be overexpressed in the tumor. Genes PMP22 and COPS3, EST AA126939 (encoding part of the hypothetical protein FLJ20343), and two anonymous ESTs (AA918483 and R02360) were found to be most consistently overexpressed after amplification. By real-time reverse transcriptase polymerase chain reaction, we could confirm the overexpression status of PMP22 and COPS3 but not of FLJ20343. We conclude that PMP22 and COPS3, and possibly also the three ESTs, are candidate amplification targets in 17p11.2 approximately p12 in osteosarcoma.
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PMID:Overexpression through amplification of genes in chromosome region 17p11.2 approximately p12 in high-grade osteosarcoma. 1519 36

Tumor suppressor gene p53 is one of the most specific genetic alterations occurring in osteosarcoma pathogenesis. It is thought to be an early and key step in the tumorigenesis of osteosarcoma. However, whether the p53 status is a marker predictive of response to therapy and a marker of prognostic value remains controversial. The choice of p53 status detection method certainly account for discrepancies. The authors used a simple functional assay (functional analysis of separated alleles in yeast) on the tumor sample of an 8-year-old girl presenting with an osteosarcoma of the tibia. While making it possible to exclude the presence of a germline mutation, FASAY indicated the presence of a somatic p53 mutation lacking transcriptional activity on p21 and bax target genes. FASAY also strongly suggested a loss of heterozygosity p53, which was confirmed by cytogenetic analysis. Sequencing of cDNA extracted from yeast colonies containing mutated p53 identified a 213 stop mutation in exon 6. Despite these p53 alterations, the child is still in complete remission after a follow-up of 48 months.
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PMID:Identification of a transcriptionally inactive p53 mutant by functional analysis of separated alleles in yeasts (FASAY) in a child osteosarcoma tumor: a case report. 1520 94

Clusterin/apolipoprotein J (CLU) is a secreted heterodimeric glycoprotein that is reportedly upregulated during tumorigenesis, as well as during cell injury or death. Despite extensive efforts, CLU function during cellular death remains largely elusive. We are using as a model system to study CLU function three human osteosarcoma (OS) cell lines, namely, Sa OS, KH OS, and U-2 OS cells, induced to die after exposure to severe genotoxic stress mediated by the chemotherapeutic drug doxorubicin (DXR). We initially applied small interfering RNA (siRNA)-mediated specific knockdown of the CLU protein in OS cells. In all three cell lines, CLU knockdown resulted in increased sensitization to DXR-induced apoptosis. Supportively, moderate levels of forced transgene-mediated CLU stable overexpression in KH OS cells could rescue them from DXR-mediated apoptosis. In contrast, stable overexpression of high CLU levels in Sa OS and U-2 OS cells augmented apoptosis induced by cell exposure to severe DXR-mediated genotoxic stress. In summary, our data provide evidence that, although CLU is essential for cellular homeostasis, it may become highly cytotoxic in certain cellular contexts when it accumulates in high amounts intracellularly either by direct synthesis or by uptake from the extracellular milieu.
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PMID:Functional analysis of clusterin/apolipoprotein J in cellular death induced by severe genotoxic stress. 1524 15


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