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

Cellular genes containing nucleotide sequences homologous to retroviral oncogenes (v-onc) have been identified in the genomes of a variety of species of both the vertebrate and invertebrate phyla. Expression of such genes, termed c-onc genes, has been shown to be tissue-specific in chickens and mice and to be modulated during murine development and differentiation of human haematopoietic cells. We report here that the level of the c-fos gene transcripts is 100-fold greater in human term fetal membranes than in other normal human tissues and cells. These levels of c-fos expression in human amniotic and chorionic cells are close to the level of v-fos expression that results in the induction of osteosarcomas in mice and transformation of fibroblasts in vitro. This observation suggests that the induction of neoplastic transformation by the FBJ murine osteosarcoma virus may require the expression of the fos gene product at high levels in an inappropriate cell type. In contrast, the human c-fms gene is expressed at high levels specifically in term placenta and trophoblastic cells. The tissue and cell type-specific patterns of c-fos and c-fms expression suggest that the physiological function of the c-fos and c-fms encoded proteins may be associated with those embryo-derived cells whose primary functions are protection and nourishment of the human fetus.
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PMID:Tissue and cell type-specific expression of two human c-onc genes. 687 68

Fifteen archival human osteosarcoma specimens were examined by in situ hybridization for the expression of human and mouse transforming growth factor-beta (isoforms 1, 2, and 3), c-fos, and metalloproteinase (stromelysin-3 and matrilysin). Osteosarcoma subtypes were confirmed by review of patients' radiographs, histopathology, and age at diagnosis. The outcome and method of treatment were documented. The subtypes of osteosarcoma consisted of nine conventional osteosarcomas and two each of fibroblastic, telangiectatic, and post-radiation osteosarcomas. Each specimen was histologically examined under light microscopy, and then adjacent paraffin sections were assayed with sense and anti-sense RNA probes by in situ hybridization. The probes localized to the neoplastic cells, confirming the methodology of the technique. Human transforming growth factor-beta 1 had the most uniform binding affinity to the osteosarcomas examined and was more specific in binding than mouse transforming growth factor-beta 1. Specific mRNA encoding for the transforming growth factor-beta s, c-fos, and metalloproteinases are detectable in patterns within osteosarcoma cells, and collectively, their expression parallels the different histopathologic subtypes. The less differentiated subtypes (telangiectatic and post-radiation osteosarcomas) expressed the fewest molecular markers. Osteosarcoma is a heterogeneous tumor. Differential expression of matrilysin in osteosarcoma is the first reported detection of metalloproteinase activity in human skeletal sarcoma.
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PMID:Osteosarcoma oncogene expression detected by in situ hybridization. 747 45

Human osteosarcoma and fibrosarcoma cell lines were investigated for alterations in oncogenes, tumor suppressor genes, and growth factors, all of which have been implicated in tumor formation. Characterization of oncogenes that are involved in osteosarcoma formation, including the c-fos and c-myc oncogenes, indicated that all six osteosarcoma cell lines examined had 5- to 20-fold amplification of the c-myc oncogene, whereas neither of two fibrosarcoma cell lines c-myc amplification. Interestingly, only three of six osteosarcoma cell lines displayed altered c-myc immediate-early gene function. c-fos was found to be normal, both at the gene and functional levels, in all six osteosarcoma and both fibrosarcoma cell lines tested. Characterization of two tumor suppressor genes, p53 and RB1, that have been implicated in osteosarcoma formation indicated that p53 was altered in five of six osteosarcoma cell lines, whereas RB1 was altered in only two or six of these cell lines. Neither RB1 nor p53 was found to be altered in the fibrosarcoma cell lines tested. An additional transformation marker, autocrine growth-factor production, was observed in all six osteosarcoma cell lines and both fibrosarcoma cell lines examined. Finally, the differentiation state of the osteosarcoma cell lines was investigated via the bone differentiation markers alkaline phosphates and osteocalcin. Alkaline phosphatase activity was observed in four of six osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined. The alkaline phosphatase activity was a result of the expression of the bone/liver/kidney alkaline phosphatase isoform. High-level osteocalcin expression was observed in one of the osteosarcoma cell lines but not in the two fibrosarcoma cell lines examined, although all cell lines demonstrated low-level osteocalcin expression. Together, these data demonstrate that relatively undifferentiated osteosarcomas commonly display c-myc amplification, p53 and RB1 mutation, and autocrine growth-factor production, all of which may play a role in osteosarcomagenesis.
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PMID:Analysis of oncogenes, tumor suppressor genes, autocrine growth-factor production, and differentiation state of human osteosarcoma cell lines. 757 9

We investigated the contribution of c-fos protooncogene in the mitogenic effect of transforming growth factor-beta (TGF beta) in serum-deprived, confluent rat calvaria osteoblastic cells. The TGF beta-induced growth in these cells was associated with an immediate and transient c-fos mRNA accumulation, similar to the inductive effect of fetal calf serum. To assess the role of c-fos in the response to TGF beta, we used a c-fos antisense (AS) oligonucleotide displaying duplex formation with rat c-fos mRNA. Studies of AS and sense (S) uptake by osteoblastic cells demonstrated that incorporation of labeled oligomers was maximal at 2 h, and the incorporated AS oligonucleotide remained intact for 24 h. Immunofluorescence analysis of c-Fos-labeled cells demonstrated that AS, but not S, oligonucleotide reduced c-Fos protein expression, suggesting specific efficient inhibition of c-fos translation by the AS oligomer. Proliferation assays showed that cell growth induced by fetal calf serum was inhibited by the AS, but not by the S oligonucleotide, in both normal rat osteoblasts and ROS 17/2.8 osteosarcoma cells, demonstrating efficient and specific blockage of cell growth by the AS oligomer. The mitogenic effect of TGF-beta was abolished in cells cultured in the presence of AS, whereas S had no effect, showing that c-fos is required for TGF beta-induced osteoblast cell growth. The results show that the induction of c-fos is implicated in the mitogenic effect of TGF beta in osteoblastic cells and provide a cellular mechanism involved in the response of these cells to TGF beta.
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PMID:c-fos protooncogene is involved in the mitogenic effect of transforming growth factor-beta in osteoblastic cells. 777 69

Using in situ hybridization we show that expression of the c-fos oncogene, a gene normally associated with osteosarcomas, is greatly elevated in osteoclasts of patients with Paget's disease. Immunohistochemical staining with c-fos antibodies also shows increased protein in pagetic osteoclasts. In light of transgenic mouse experiments showing a key role for c-fos in bone resorption, we propose that elevated c-fos gene expression in pagetic osteoclasts is an important component in producing the pagetic phenotype. Levels of c-fos gene and protein expression in pagetic osteoblasts are lower than those detected in osteoclasts but still higher than in nonpagetic osteoblasts. This may provide an explanation for the increased incidence of osteosarcomas in patients with Paget's disease because overexpression of c-fos in osteoblasts of transgenic mice induces osteosarcoma formation.
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PMID:Upregulation of c-fos protooncogene expression in pagetic osteoclasts. 797 1

The binding of transcription factor AP-1 and vitamin D receptor (VDR) to the composite AP-1 plus vitamin-D-responsive promoter region (AP-1 + VDRE) of the human osteocalcin gene was characterized in osteocalcin-producing (MG-63) and non-producing (U2-Os, SaOs-2) human osteosarcoma cell lines. In mobility-shift assays with AP-1 + VDRE, AP-1, and VDRE probes and nuclear extracts from these cells, one AP-1-specific and two VDR-specific (fast and slow mobility) interactions were observed. Characterization of the complexes indicated that AP-1 and VDR do not bind simultaneously to the AP-1 + VDRE oligonucleotide. Intensity of the complexes was greatly influenced by cell density: in MG-63 and SaOs-2 cells, AP-1 binding was strong during the proliferative period disappearing at confluency whereas, in U2-Os cells, AP-1 binding was prominent also at the confluent stage. Furthermore, MG-63 cells possessed the faster migrating VDR complex at all stages of confluency whereas, in U2-Os and SaOs-2 cells, it was very weak or absent. There were no detectable differences in the levels of VDR protein between these cell lines. In U2-Os cells, the level of c-jun mRNA was higher than in the other two cell lines, whereas none of these cell lines exhibited detectable levels of c-fos mRNA at the confluent stage. Exogenous c-Jun protein effectively blocked the VDR-DNA interaction. Further, all these cell lines expressed mRNA for retinoid X receptor alpha (RXR alpha), the factor suggested to be required for the VDR-DNA interaction. The presence of an accessory factor in the VDR-DNA complexes was indirectly shown by treatment of the cells with 9-cis retinoic acid and by cycloheximide. Both treatments reduced VDR binding without affecting the VDR protein level. These results suggest that AP-1 interferes with VDR binding to the AP-1 + VDRE element and that the vitamin D responsiveness of the osteocalcin gene correlates with weak AP-1 binding and strong binding of the faster migrating VDR complex.
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PMID:Functional interference between AP-1 and the vitamin D receptor on osteocalcin gene expression in human osteosarcoma cells. 807 31

We have shown previously that overexpression of c-Ha-ras, v-mos or c-fos increases the spontaneous level of chromosomal aberrations and gene mutations in NIH 3T3 cells, and that reduction of the Fos protein level inhibits aberration induction by c-Ha-ras and v-mos and also by irradiation with ultraviolet light (van den Berg et al., Mol. Carcinogenesis, 4, 460-466). In order to examine whether fos is also involved in DNA recombination, thymidine kinase (tk) deficient human osteosarcoma cells containing two versions of the herpes simplex virus tk gene inactivated by base insertion were either transiently or stably transfected with various fos expression plasmids. The frequency of tk+ revertants was significantly enhanced both upon transient transfection with RSV-promoter-fos gene constructs and by stimulation of Fos synthesis in stably transfected cells harbouring an inducible metallothionein promoter-fos construct. No such increases were observed in cells transfected with plasmids containing a truncated version of c-fos. The data indicate that c-fos is involved in generating various types of genetic changes including homologous recombination; a role of c-fos in genetic instability may contribute to its action in tumor promotion and progression.
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PMID:Overexpression of c-fos increases recombination frequency in human osteosarcoma cells. 809 16

The human osteosarcoma cell culture HOS does not produce matrix metalloproteinases (MPs). However, after transformation with the Ki-ras oncogene, the resulting culture (KHOS) produced readily detectable MPs. The molecular weight of the major MP was 66 kDa, while the molecular weights of two other minor bands were 71 kDa and 60 kDa. The activity of all three enzymes was inactivated by treatment with ethylene diaminetetra acetic acid, indicating that they are probably MPs. The substrate preference of the 66-kDa MP (in decreasing order) was gelatin and collagens V, I, III, and IV. Treatment of the MPs with p-aminophenylmercuric acetate led to the appearance of 62-kDa activated enzyme. The MP produced by KHOS cells did not react with the monoclonal anti-rat stromelysin antibody MC. Treatment of KHOS cells with retinoic acid and dexamethasone, which are known to suppress c-fos/c-jun and AP-1, suppressed the production of the MPs. Therefore, the activation of MPs by Ki-ras in KHOS cells may involve c-fos/c-jun and the AP-1-responsive pathway.
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PMID:Activated production of metalloproteinases in Ki-ras-transformed human osteosarcoma cells. 815 1

The proto-oncogene transcription factors Fos and Jun form a heterodimeric complex that binds to DNA and regulates expression of specific target genes. Continuous expression of c-fos causes transformation of cultured fibroblasts and induces osteogenic sarcoma in mice. To investigate the molecular basis of fos-mediated oncogenesis, we developed a conditional cell transformation system in which Fos expression was regulated by isopropyl-beta-D-thiogalactopyranoside (IPTG). Synthesis or repression of Fos in L1-3c-fos cells occurred rapidly, within 30 min, after the removal or addition of IPTG to the culture medium. However, there was a significant delay between the induction of Fos expression and the appearance of morphological transformation. No effect was observed after 12 h of Fos expression, partial transformation was detected after 24 h, and full transformation required approximately 3 days of continuous Fos expression. Similarly, the transformed cell morphology persisted for at least 2 days after repression of Fos, and a normal phenotype was observed only after 3 days. Fos-Jun complexes, capable of binding to AP-1 sequences, were present continuously during the delay in morphological transformation. Furthermore, increased expression of several candidate Fos target genes, including those encoding Fra-1, transin (stromelysin), collagenase, and ornithine decarboxylase, was detected shortly after Fos induction. The induction of morphological transformation was not dependent on the cell cycle, as it occurred in both cycling and noncycling cells. Thus, the Fos-Jun complexes present before L1-3c-fos cells become fully transformed are transcriptionally active. These complexes disappeared, and the Fos target genes were repressed at least 2 days prior to reversion. Our results suggest that cell transformation by Fos requires increased expression of a target gene(s) with a long-lived product(s) that must reach a critical level.
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PMID:Cell transformation by c-fos requires an extended period of expression and is independent of the cell cycle. 819 66

Alkaline phosphatase (AP) activity and expression of bone Gla protein (BGP), c-fos, and c-jun were compared in two transplantable osteosarcomas with high potentials for metastasis to the lung. The original spontaneous osteosarcoma (SOS) gradually became histologically undifferentiated, losing its osteogenic activity during serial transfer, whereas the chemical (4-hydroxyaminoquinoline 1-oxide)-induced osteosarcoma (COS) retained osteogenesis. The two osteosarcomas showed similar doubling times and levels of lung metastasis, and strong AP activity was detected on the cell membranes of both. Northern blot analysis revealed that lack of BGP mRNA expression was associated with expression of both c-fos and c-jun proto-oncogenes in SOS. In contrast, neither c-fos nor c-jun mRNAs were detected but BGP mRNA was expressed in the case of COS. These results suggest that the c-fos and c-jun genes may suppress the expression of BGP mRNA relevant to differentiation and osteoid formation in rat osteosarcomas. However, this does not appear to be directly related to proliferative or metastatic biological behavior.
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PMID:Correlation between lack of bone Gla protein mRNA expression in rat transplantable osteosarcomas and expression of both c-fos and c-jun proto-oncogenes. 845 89


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