UMLS:C0029463 - FACTA Search

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Query: UMLS:C0029463 (osteosarcoma)
16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One important mechanism by which multidrug resistance is mediated is the mdr1 gene product, P-glycoprotein (Pgp). Even though chemotherapy, in the treatment of high grade central osteosarcoma (hgc-OS), has led to dramatic improvements in survival rate, a certain percentage of patients still show only a poor response to chemotherapy. To further characterize a potential connection between Pgp and chemotherapy as well as the role of Pgp in tumorigenesis of osteosarcoma, we analyzed Pgp-expression in hcg-OS. Immunohistochemistry was performed on 68 hgc-OS samples from 58 patients using the monoclonal antibody JSB-1; in addition, Pgp-expression in normal bone cells was studied in 5 human epiphyseal growth plates. 70.5% of all cases stained positive for P-glycoprotein, while 29.5% of the cases were negative. Cases investigated after chemotherapy showed a higher incidence (82.9%) of positive P-glycoprotein immunostaining than cases prior to chemotherapy (64.4%). The Pgp-expression of 34 biopsies was compared with chemotherapy, as determined at the surgical specimen. In these cases, however, no correlation could be established between P-glycoprotein expression of the biopsy and the later response to chemotherapy. 48.4% of the cases with biopsies, initially positive for Pgp, showed a good response in the surgical specimen, while only 27.2% of Pgp-positive biopsies were later classified as non-responders. In the normally growing skeleton, positive immunostaining was detected in the area of mineralization of epiphyseal growth plates. Osteoclasts, hypertrophic chondrocytes, and cuboidal osteoblasts showed Pgp-expression, while there was a lack of Pgp in the majority of osteocytes and chondrocytes in the resting and proliferating zone. These data therefore suggest that P-glycoprotein expression in hgc-OS resembles, at least in part, the phenotype of active bone cells. These results may explain why P-glycoprotein, by using immunohistochemistry, in biopsies of osteosarcomas is insufficient to predict the response to chemotherapy.
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PMID:P-glycoprotein expression in high grade central osteosarcoma and normal bone cells. An immunohistochemical study. 922 55

The til-1 locus was identified as a common retroviral integration site in virus-accelerated lymphomas of CD2-myc transgenic mice. We now show that viral insertions at til-1 lead to transcriptional activation of PEBP2alphaA (CBFA1), a transcription factor related to the Drosophila segmentation gene product, Runt. Insertions are upstream and in the opposite orientation to the gene and appear to activate a variant promoter that is normally silent in T cells. Activity of this promoter was detected in rodent osteogenic sarcoma cells and primary osteoblasts, implicating bone as the normal site of promoter activity. The isoforms encoded by the activated gene all encompass the conserved runt DNA-binding domain and share a novel N terminus different from the previously reported PEBP2alphaA products. Minor products include isoforms with internal deletions due to exon skipping and a novel C-terminal domain unrelated to known runt domain factors. The major isoform expressed from the activated til-1 locus (G1) was found to account for virtually all of the core binding factor activity in nuclear extracts from its corresponding lymphoma cell line. Another member of this gene family, AML1(CBFA2), is well known for its involvement in human hemopoietic tumors. These results provide evidence of a direct oncogenic role for PEBP2alphaA and indicate that the Myc and Runt family genes can cooperate in oncogenesis.
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PMID:Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): evidence for a new myc collaborating oncogene. 923 31

A deletion in the tumor-suppressor gene, RB, discovered by quantitative multiplex PCR, shows low penetrance (LP), since only 39% of eyes at risk in this family develop retinoblastoma. The 4-kb deletion spanning exons 24 and 25 (delta24-25) is the largest ever observed in an LP retinoblastoma family. Unlike the usual RB mutations, which cause retinoblastoma in 95% of at-risk eyes and yield no detectable protein, the delta24-25 allele transcribed a message splicing exon 23 to exon 26, resulting in a detectable protein (pRBdelta24-25) that lacks 58 amino acids from the C-terminal domain, proving that this domain is essential for suppression of retinoblastoma. Two functions were partially impaired by delta24-25-nuclear localization and repression of E2F-consistent with the idea that LP mutations generate "weak alleles" by reducing but not eliminating essential activities. However, delta24-25 ablated interaction of pRB with MDM2. Since a homozygous LP allele is considered nontumorigenic, the pRB/MDM2 interaction may be semi- or nonessential for suppressing retinoblastoma. Alternatively, some homozygous LP alleles may not cause tumorigenesis because an additional event is required (the "three-hit hypothesis"), or the resulting imbalance in pRB function may cause apoptosis (the "death allele hypothesis"). pRBdelta24-25 was also completely defective in suppressing growth of Saos-2 osteosarcoma cells. Targeting pRBdelta24-25 to the nucleus did not improve Saos-2 growth suppression, suggesting that C-terminal domain functions other than nuclear localization are essential for blocking proliferation in these cells. Since delta24-25 behaves like a null allele in these cells but like an LP allele in the retina, pRB may use different mechanisms to control growth in different cell types.
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PMID:Deletion of RB exons 24 and 25 causes low-penetrance retinoblastoma. 932 21

Treatment for osteosarcoma is problematic because there are no prognostic markers. Diagnosis is primarily limited to cytologic grading. Oncogenesis alters cell structure therefore osteoblast tissue matrix proteins (extracellular matrix, cytoskeletal, intermediate filament, and nuclear matrix proteins), components of the cell substructure, are candidates for osteosarcoma markers. Structural proteins of the extracellular matrix, e.g. the collagens, are useful for diagnosis but not for tumors that produce little osteoid. To identify principal cellular tissue matrix proteins that distinguish normal from transformed human osteoblasts, their expression in normal osteoblasts, two osteosarcoma cell lines, and three primary osteosarcoma tumors were compared. The tumors were graded as (i) intermediate, (ii) high, and (iii) high grade recurrent. The 1-D SDS/PAGE profiles of the major components of the nuclear matrix and intermediate filament fractions from normal osteoblasts did not vary with biopsy site, age, or sex of patients. These profiles included known cytoskeletal proteins and OB250, a approximately 250 kD protein(s) observed in the intermediate filament fraction. A loss of protein bands, including OB250, was observed in the osteosarcoma cell lines and tumors. The intermediate and high grade tumors exhibited nearly identical protein profiles including potential tumor-specific proteins and collagen, consistent with the presence of intracellular collagen fibers in osteosarcoma. A microsequence was obtained for OT25, a novel low molecular weight protein observed in osteosarcoma cell lines. Fibrinogen gamma-chain, a protein that mediates cell adhesion was recovered from the high grade recurrent tumor.
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PMID:Tissue matrix protein expression in human osteoblasts, osteosarcoma tumors, and osteosarcoma cell lines. 940 69

Inactivation of the p53 tumor suppressor gene has been implicated in the pathogenesis of numerous human cancers, including osteosarcomas. Appendicular osteosarcomas of the dog appear to be a good model for their human equivalent with regard to biologic behavior, epidemiology and histopathology. We individually screened exons 5-8 of the p53 gene for mutations in 15 canine appendicular osteosarcomas using 'Cold' SSCP to compare the role of this gene in human and canine osteosarcoma tumorigenesis. Seven of the tumors (47%) exhibited point mutations, with one tumor possessing two mutations within different exons. Of these, seven were missense mutations and the eighth was a 'silent' mutation potentially affecting the exon 6-7 splicing region. Five of the missense mutations were located in highly conserved regions IV and V, while another corresponded with the highly conserved codon 220 mutational hotspot located outside the conserved domains. The locations and types of mutations were nearly identical to those reported in human cancer. These findings provide strong evidence of the involvement of p53 mutations in the development of canine appendicular osteosarcomas. Canine osteosarcomas appear to be a promising model for their human equivalent on a clinical, pathologic, and molecular level.
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PMID:Mutation of the p53 tumor suppressor gene in spontaneously occurring osteosarcomas of the dog. 947 14

The insulin-like growth factor-I receptor (IGF-IR) is involved in tumorigenesis. The aim of the present study was to investigate whether the IGF-IR is a physiological target for p53 in osteosarcoma cells. The p53-induced regulation of IGF-IR levels was studied in a tetracycline-regulated expression system. When expressed in Saos-2, osteosarcoma cells that lack p53, wild-type p53 decreased, whereas mutated p53 increased IGF-IR expression, and IGF-I-induced tyrosine phosphorylation of the IGF-IR. Similarly, wild-type p53 decreased IGF-I-induced tyrosine phosphorylation of IRS-1. A functional and physical interaction between p53 and Sp1, in the regulation of the IGF-R, was studied in osteosarcoma cells. Expression of p53 decreased IGF-IR promoter activity, whereas no effect on promoter activity was seen by Sp1 expressed alone. However, Sp1 counteracted the inhibitory effect of p53 on IGF-IR promoter activity in a dose-dependent manner. Furthermore, wild-type and mutated p53 were coimmunoprecipitated with Sp1, indicating a physical interaction between p53 and Sp1. In conclusion, p53 regulates IGF-IR expression, as reflected by a reduction in IGF-IR protein and a parallel reduction in IGF-I-induced tyrosine phosphorylation of the IGF-IR and IRS-1 in an osteosarcoma cell line. These data indicate that the IGF-I receptor is a physiological target for p53 in osteosarcoma cells. Furthermore, data supporting an interaction between p53 and Sp1 in the regulation of the promoter activity of IGF-IR are presented.
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PMID:p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. 949 43

Simian virus 40 (SV40) is an oncogenic virus which induces tumors in hamsters and transforms human cells in tissue culture. Between 1955 and 1963, polio vaccines and adenovaccines were contaminated with SV40; therefore, millions of people were exposed to this oncogenic virus. The SV40 proteins responsible for in vivo oncogenesis and in vitro cell transformation are encoded by the early region of the virus. These proteins are called T (tumor) antigens (Tags), because animals with tumors induced by SV40 have antibodies against these viral proteins. Recently, we and other research laboratories have found SV40 in specific types of human tumors: mesothelioma, ependymoma and choroid plexus tumors, osteosarcoma and sarcoma. The same tumor types will develop in hamsters which have been injected systemically with SV40. SV40 causes cell transformation in tissue culture and tumors in animals, because SV40 Tag binds and inactivates the cellular tumor suppressor gene products, Rb and p53. We found that SV40 Tag binds p53 and Rb in human mesotheliomas, possibly contributing to the malignant phenotype.
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PMID:The biological activities of simian virus 40 large-T antigen and its possible oncogenic effects in humans. 968 8

The retinoblastoma (RB) gene is one of the most extensively studied tumour-suppressor genes. Deletion or inactivation of both RB alleles is an essential, rate-limiting step in the formation of retinoblastoma and osteosarcoma that arise in families that carry mutant RB (ref. 2). RB inactivation is also found in other human tumours. Whereas loss of RB function is associated with the loss of cellular proliferative control, introduction of a wild-type RB can suppress cell growth and tumorigenicity. Thus, identification of factors that interfere with and/or control the function of the RB protein is critical for understanding both cell-cycle control and oncogenesis. Here we describe a new gene, Bog (for B5T over-expressed gene), which was identified and shown to be overexpressed in several transformed rat liver epithelial (RLE) cell lines resistant to the growth-inhibitory effect of TGF-beta1, as well as in primary human liver tumours. The Bog protein shares homology with other retinoblastoma-binding proteins and contains the Rb-binding motif LXCXE. Using the yeast two-hybrid system and co-immunoprecipitation, we demonstrated that Bog binds to Rb. In vivo, Bog/Rb complexes do not contain E2F-1, and Bog can displace E2F-1 from E2F-1/Rb complexes in vitro. Overexpression of Bog in normal RLE cells conferred resistance to the growth-inhibitory effect of TGF-beta1. Furthermore, normal RLE cells are rapidly transformed when Bog is continuously overexpressed and form hepatoblastoma-like tumours when transplanted into nude mice. These data suggest that Bog may be important in the transformation process, in part due to its capacity to confer resistance to the growth-inhibitory effects of TGF-beta1 through interaction with Rb and the subsequent displacement of E2F-1.
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PMID:A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability. 969 99

The c-myc and c-fos proto-oncogenes have several putative functions, including regulation of cell growth. In many neoplasms c-myc overexpression has been linked to poor prognosis. In order to study the role of c-myc and c-fos expression on the tumorigenesis, and the metastatic spread of osteosarcoma, frozen and paraffin-embedded tissue 38 primary osteosarcoma and 10 lung metastases were analyzed. The mRNA analysis was performed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. The protein expression was studied by Western blot analysis and immunohistochemistry. C-myc and c-fos were found overexpressed in a high percentage of the relapsed tumors and of the metastases, and overexpression of both oncogenes in the same tumor was strongly correlated to the development of metastases (p < 0.05), as 6 of the 7 primary tumors overexpressing both the oncogenes gave metastases. In conclusion, both c-myc and c-fos are involved in the growth and spread of osteosarcoma and a synchronous overexpression of both oncogenes is highly significant for a metastatic potential of a primary tumor.
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PMID:C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. 977 23

Alterations in tumor suppressor gene p53, localized on chromosome 17p13, are considered to play a significant role in the initiation and, to some extent, even in the progression of various malignant tumors. In this respect, investigations on conventional highly malignant osteosarcomas have shown a mutation rate of approximately 20%. However, currently, data on the mutation rate in the group of variant histology osteosarcomas of low-grade malignancy do not exist. Therefore, we investigated a panel of low malignant entities (five low malignant intramedullary osteosarcomas grade 1; one intramedullary osteosarcoma grade 2; eight parosteal osteosarcomas, including one local recurrence grades 1 and 2, and five periosteal osteosarcomas grade 2) with polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) analysis focusing on exons 4 to 8 of the p53 gene followed by direct sequencing. Point mutations were found in one low-grade osteoblastoma-like osteosarcoma and in two periosteal osteosarcomas grade 2 (one missense, one silent, and one nonsense mutation). This mutation rate of 15.7% (3 of 19) is comparable to that determined in highly malignant osteosarcomas. Moreover, the analysis of clinical data did not show any difference in the behavior of tumors with p53 mutations compared with those without. Therefore, we suggest that alterations in p53 gene are an early event in the tumorigenesis of malignant osteoblastic tumors without impact on progression of these tumors.
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PMID:p53 gene mutations in osteosarcomas of low-grade malignancy. 982 13

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