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)

The peripheral myelin protein (PMP22) gene is highly expressed in peripheral Schwann cells and encodes an important constituent of the myelin sheath. It is also expressed at lower levels in other normal tissues in which the protein is supposed to be involved in cell growth regulation. We recently reported frequent amplification and overexpression of PMP22 in high-grade osteosarcoma. Here, we analyzed PMP22 expression in five osteosarcoma tumors and three osteosarcoma cell lines. In normal Schwann cells, transcription of PMP22 starts at three promoters, P1A, P1B, and P2, which results in the synthesis of three alternatively spliced transcripts that all code for the same protein. We found a comparable expression pattern in normal osteoblasts. However, promoter P1A-driven transcripts were absent in all investigated tumors and cell lines and, compared to normal osteoblasts, the P1B/P2 transcript ratio was found to be increased in two of three cases with PMP22 overexpression and decreased in all five cases without overexpression. In normal Schwann cells and in NIH3T3 cells, PMP22 expression increases upon serum starvation-induced growth arrest. In contrast to this, serum withdrawal caused a considerable decrease of PMP22 expression in the osteosarcoma cell lines. We conclude that the different PMP22 expression in osteosarcoma may result in alternative availability of the PMP22 protein during the cell cycle and aberrant regulation of cell growth control in osteosarcoma tumorigenesis.
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PMID:Characterization of PMP22 expression in osteosarcoma. 1526 28

Formalin-fixed paraffin embedded (FFPE) tumor tissue provides an opportunity to perform retrospective genomic studies of tumors in which chromosomal imbalances are strongly associated with oncogenesis. The application of comparative genomic hybridization (CGH) has led to the rapid accumulation of cytogenetic information on osteosarcoma (OS); however, the limited resolving power of metaphase CGH does not permit precise mapping of imbalances. Array CGH allows quantitative detection and more precise delineation of copy number aberrations in tumors. Unfortunately the high cost and lower density of BACs on available commercial arrays has limited the ability to comprehensively profile copy number changes in tumors such as OS that are recurrently subject to genomic imbalance. In this study a cDNA/EST microarray including 18,980 human cDNAs (which represent all 22 pairs of autosomal chromosomes and chromosome X) was used for CGH analysis of eight OS FFPE. Chromosomes 1, 12, 17, and X harbored the most imbalances. Gain/amplification of X was observed in 4/8 OS, and in keeping with other recent genomic analyses of OS, gain/amplification of 17p11.2 was often accompanied by a distal deletion in the region of the p53 gene. Gain/amplification of the X chromosome was verified using interphase FISH carried out on a subset of OS FFPE sections and OS tissue arrays.
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PMID:High-resolution cDNA microarray CGH mapping of genomic imbalances in osteosarcoma using formalin-fixed paraffin-embedded tissue. 1530 59

Low-grade central osteosarcoma is an uncommon form that is characterized by a long premorbid history, and is compatible with prolonged survival after treatment. However, molecular abnormalities are rare in low-grade central osteosarcomas, whereas p53 mutations occur in approximately 20% of conventional high-grade osteosarcomas. In this study, 21 cases of low-grade central osteosarcoma were analyzed for mutations of the p53 gene, amplification of the MDM2 gene, and mutations of the H-ras gene using formalin-fixed, paraffin-embedded materials. We also examined the expression of p53, MDM2, and p21WAF1 protein immunohistochemically and assessed the proliferation activities using the monoclonal antibody MIB-1. One case (4.7%) showed strong p53 immunoreactivity, whereas p53 gene mutations were not detected at all. Seven cases (33.3%) showed immunoreactivity for MDM2 protein. As for gene alterations, MDM2 amplification was found in four cases (19.0%). p21WAF1 expression was detected in 12 cases (57.1%). MIB-1-LI showed very low levels in all the cases and no significant correlation with p53 or MDM2 immuno-reactivity. None of the tumors showed H-ras mutations. In conclusion, the number of p53 gene alterations in low-grade central osteosarcomas is lower than that in conventional high-grade osteosarcomas. MDM2 alterations and p21WAF1 expression might be involved in the tumorigenesis of low-grade central osteosarcomas.
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PMID:Molecular analysis of p53, MDM2 and H-ras genes in low-grade central osteosarcoma. 1531 Jan 47

We summarize and briefly discuss recent findings with respect to the amplification and overexpression of candidate oncogenes in 17p11.2 ~p12 in high-grade osteosarcomas. Amplification of this region occurs in about 25% of cases. The amplification profiles are often complex and suggest the involvement of more than one oncogene. The 17p11.2 ~ p12 region harbors many low-copy repeats (LCRs). We propose LCR-mediated repeated duplication by mitotic nonallelic homologous recombination as mechanism for the generation of the amplifications in this region. Genes PMP22 and COPS3 and three expressed sequence tags from within 17p11.2 ~ p12 have been found to be frequently overexpressed and consistently overexpressed after amplification, which identifies them as candidate oncogenes in this region. Overexpression of COPS3 has been linked to TP53 protein degradation and, being equivalent to TP53 mutation, the induction of genomic instability, which frequently occurs in high-grade osteosarcoma. These findings may serve as a framework for future work aimed to identify the causative oncogenes in 17p11.2 ~p12, to clarify the mechanism of their amplification, and to determine their importance in osteosarcoma tumorigenesis.
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PMID:Amplification and overexpression of genes in 17p11.2 ~ p12 in osteosarcoma. 1532

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
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PMID:Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. 1558 32

Mice lacking both p18(Ink4c) and p27(Kip1) develop a tumor spectrum similar to pRb(+/-) mice, and loss of p53 function accelerates tumorigenesis in pRb(+/-) mice. We hypothesized that codeletion of either p18 or p27 in conjunction with p53 deletion will also accelerate tumorigenesis. Mice lacking both p18 and p53 develop several tumors not reported in either single null genotype, including hepatocellular carcinoma, testicular choriocarcinoma, hemangiosarcoma, leiomyosarcoma, fibrosarcoma, and osteosarcoma. Mice lacking both p27 and p53 exhibit a decreased lifespan and develop unique tumors, including papillary carcinoma of the colon, hemangiosarcoma, and leiomyosarcoma. In both p18/p53 and p27/p53 double null genotypes, the incidence and spectra of tissues that develop lymphoma are also increased, as compared to the single null genotypes. The development of p27/p53 double null colon tumors correlates with secondary changes in cell-cycle protein expression and CDK (cyclin-dependent kinase) activity, perhaps contributing to the progression of colorectal cancer. We concluded that p18 and p27 can, not only functionally collaborate with one another, but also can independently collaborate with p53 to modulate the cell cycle and suppress tumorigenesis in a tissue-specific manner.
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PMID:Tumorigenesis in p27/p53- and p18/p53-double null mice: functional collaboration between the pRb and p53 pathways. 1558 24

Osteosarcoma is a malignant bone tumor that commonly affects adolescents and young adults. In the present study a human osteosarcoma cell line, KTHOS, was established from a primary osteosarcoma lesion in the distal femur of a 16-year-old girl. After 106 passages, the KTHOS cell line retained the biological characteristics of osteosarcoma. The KTHOS cells had spindle to pleomorphic cytoplasm with round to ovoid nuclei containing multiple prominent nucleoli, as expected based on the mesodermic origin of osteoblasts. The KTHOS cells were immunoreactive for osteocalcin, osteonectin, stem cell factor (SCF), and KIT (CD117). Reverse transcriptase-polymerase chain reaction indicated that the KTHOS cell line expressed mRNA for SCF and KIT. The KTHOS cells produced relatively high amounts of soluble SCF as determined by enzyme-linked immunosorbent assay. The results suggest that cell proliferation of the KTHOS cell line might be involved in autocrine and/or paracrine loops of the SCF/KIT signaling system. The KTHOS cell line is a novel human osteosarcoma cell line that releases SCF and expresses KIT. This cell line can be used for studies to explore the mechanisms for oncogenesis of human osteosarcomas.
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PMID:Establishment and characterization of a KIT-positive and stem cell factor-producing cell line, KTHOS, derived from human osteosarcoma. 1569 48

Constitutional molecular defects are known to play a role in oncogenesis, as shown by the increased incidence of embryonic cancers in children with Beckwith-Wiedemann syndrome (BWS) or of leukemia in children with Down syndrome. To establish the incidence and spectrum of malformation syndromes associated with childhood cancer we performed a clinical morphological examination on a series of 1,073 children with cancer. We diagnosed a syndrome in 42 patients (3.9%) and suspected the presence of a syndrome in another 35 patients (3.3%), for a total of 7.2%. This incidence of patients with a proven or suspected syndrome is high, and points to a possible association. We describe new syndrome-tumor associations in several entities: cleidocranial dysostosis (Wilms tumor), Bardet-Biedl syndrome (BBS) (acute lymphoblastic leukemia), Kabuki syndrome (neuroblastoma), LEOPARD syndrome (neuroblastoma), Poland anomaly (osteosarcoma; Hodgkin disease), and blepharophimosis epicanthus inversus syndrome (Burkitt lymphoma). Twenty of the 42 syndrome diagnoses were not recognized in the patients prior to this study, indicating that these diagnoses are commonly missed. We propose that all children with a malignancy should be examined by a clinical geneticist or a pediatrician skilled in clinical morphology to determine if the patients have a malformation syndrome.
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PMID:High incidence of malformation syndromes in a series of 1,073 children with cancer. 1653 61

CtIP interacts with a group of tumor suppressor proteins including RB (retinoblastoma protein), BRCA1, Ikaros, and CtBP, which regulate cell cycle progression through transcriptional repression as well as chromatin remodeling. However, how CtIP exerts its biological function in cell cycle progression remains elusive. To address this issue, we generated an inactivated Ctip allele in mice by inserting a neo gene into exon 5. The corresponding Ctip(-/-) embryos died at embryonic day 4.0 (E4.0), and the blastocysts failed to enter S phase but accumulated in G(1), leading to a slightly elevated cell death. Mouse NIH 3T3 cells depleted of Ctip were arrested at G(1) with the concomitant increase in hypophosphorylated Rb and Cdk inhibitors, p21. However, depletion of Ctip failed to arrest Rb(-/-) mouse embryonic fibroblasts (MEF) or human osteosarcoma Saos-2 cells at G(1), suggesting that this arrest is RB dependent. Importantly, the life span of Ctip(+/-) heterozygotes was shortened by the development of multiple types of tumors, predominantly, large lymphomas. The wild-type Ctip allele and protein remained detectable in these tumors, suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Taken together, this finding uncovers a novel G(1)/S regulation in that CtIP counteracts Rb-mediated G(1) restraint. Deregulation of this function leads to a defect in early embryogenesis and contributes, in part, to tumor formation.
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PMID:Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. 1583 59

This paper analyzes data for the osteosarcoma incidence in life-time experiments of (224)Ra injected mice with respect to the importance of initiating and promoting action of ionizing high LET-radiation. This was done with the biologically motivated two step clonal expansion (TSCE) model of tumor induction. Experimentally derived osteosarcoma incidence in 1,194 mice following exposure to (224)Ra with different total radiation doses and different fractionation patterns were analyzed together with incidence data from 1,710 unirradiated control animals. Effects of radiation on the initiating event and on the clonal expansion rate, i.e. on promotion were found to be necessary to explain the observed patterns with this model. The data show a distinct inverse protraction effect at high doses, whereas at lower doses this effect becomes insignificant. Such a behavior is well reproduced in the proposed model: At dose rates above 6 mGy/day a longer exposure produces higher ERR per dose, while for lower rates the reverse is the case. The TSCE model permits the deduction of several kinetic parameters of a postulated two-step bone tumorigenesis process. Mean exposure rates of 0.13 mGy/day are found to double the baseline initiation rate. At rates above 100 mGy/day, the initiation rate decreases. The clonal expansion rate is doubled at 8 mGy/day, and it levels out at rates beyond 100 mGy/day.
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PMID:Bone cancer risk in mice exposed to 224Ra: protraction effects from promotion. 1586 14


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