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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.
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PMID:Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. 1121 98

We investigated a lipoma and a well-differentiated/dedifferentiated liposarcoma (WD/DDL), occurring simultaneously in one patient for the possible role of p53 and mdm2 in the molecular oncogenesis of liposarcoma and tumor progression. The hypothesis tested was if there is a continuum in the development from lipoma to liposarcoma. Lipoma was characterized by a lack of p53 mutation, p53 LOH and p53 protein expression, as well as by mdm2 amplification and mdm2 protein expression. p53 mutation and p53 LOH were found neither in the well-differentiated nor in the dedifferentiated parts of the liposarcoma. In contrast, mdm2 amplification and an increase in mdm2 protein expression were found to be associated with malignancy and dedifferentiation, whereas p53 protein expression was only slightly increased. These findings indicate that mdm2 constitutes one of the most common targets for molecular aberration in WD/DDL. We suggest that mdm2 is a marker distinguishing between ordinary lipoma and well-differentiated liposarcoma, and that the genesis of these tumors is different.
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PMID:Distinction between lipoma and liposarcoma by MDM2 alterations: a case report of simultaneously occurring tumors and review of the literature. 1151 50

Mdm2 is an oncogene that binds to and inactivates the tumor suppressor p53. However, the presence of oncogenic splice variants of mdm2 in human tumors that lack the p53 binding site has suggested a p53-independent transforming function for this protein. This report describes expression of 11 different mdm2 splice variants in pediatric rhabdomyosarcoma (RMS) cell lines and tumors at a frequency of 75% and 82%, respectively. Five of these isoforms have previously been described in other tumor histiotypes but six are novel and may be unique to RMS. There was no association between expression of splice variants and mdm2 gene amplification or p53 status. In addition, the frequency of splice variants was much higher than the incidence of mdm2 amplification or p53 mutations. These variants may be important to consider with respect to RMS tumor progression and therapeutic response.
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PMID:Novel mdm2 splice variants identified in pediatric rhabdomyosarcoma tumors and cell lines. 1193 8

Oral squamous cell carcinomas (OSCC) are malignant tumors with a poor prognosis and low long-term survival rates, even when using modern adjuvant and neoadjuvant therapy forms in addition to surgery. For the clinical estimation of each tumor, it is necessary to define stage-dependent molecular and/or cellular parameters as it is known that OSCC develop along a multistep pathway including the loss of tumor suppressor genes and the amplification of oncogenes which result in changes in protein expression. In order to establish a reliable pattern of molecular and cellular biomarkers, a large number of tumor specimens from different stages of the disease need to be analysed. In this study, biopsies of a collective of 293 OSCC in different stages were screened with the novel technique of tissue chip microarrays by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). FISH-analysis was performed on the oncogene cyclin D1 and IHC-analysis on the proteins cyclin D1, p53, p16, cdk4, bcl2, mdm2 and rb. Tissue chip technology was shown to facilitate rapid screening for molecular and cellular alterations in different stages of OSCC and revealed reliable and reproducible results that may allow the definition of a multistep pathway model for tumor progression in OSCC.
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PMID:[Opportunities and chances for tissue chip microarrays in head and neck surgery. A novel technique for the rapid evaluation of potentially novel biomarkers]. 1244 51

Like malignant fibrous histiocytoma (MFH), dedifferentiated liposarcoma represents a distinct subtype of liposarcoma and is characterized by an abrupt transition from well-differentiated liposarcoma (WDL) to highgrade dedifferentiated liposarcoma (DDL) . In addition, specific cytogenetic aberrations support the close biological relationship between WDL and DDL. Recent observations indicated the significance of cell cycle aberrations in tumor progression from the low-malignant, well differentiated to its dedifferentiated form, the prognosis of which is poor. Thus, alterations of mdm2 and p53 genes belong to the most frequently reported alterations in these two subtypes of liposarcoma. In previous investigations, we reported that loss of heterozygosity at the Rb gene locus, telomerase activity, hTERT, and c-Myc expression were associated with tumor progression in liposarcomas. In this study, we report on a case of a WD/DDL, in which both tumor components were separated using laser microdissection (P.A.L.M.) for the investigation of hTERT mRNA expression on a LightCycler. Macroscopically selected and histologically proven cryosections of low malignant and highly malignant tumor areas were cytogenetically investigated to confirm the diagnosis and to find additional chromosomal alterations with tumor progression.
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PMID:Different mRNA expression profile during tumor progression in a well-differentiated liposarcoma--A microdissection approach. 1292 48

5-lipoxygenase (5-LO) promotes cancer cell proliferation and survival by unclear mechanisms. Here, we show that 5-LO expression and activity were induced by genotoxic agents in a p53-independent manner and antagonized p53- or genotoxic drug-induced apoptosis in a variety of cancer cells. 5-LO inhibited p53-governed transactivation of the pro-apoptotic genes bax and pig3 but not of p21(WAF1/CIP1) or mdm2. This may be explained by 5-LO capability to inhibit the binding of p53 to promyelocytic leukemia protein (PML) and p53 subnuclear relocalization into PML-nuclear bodies in response to genotoxic stress. Interestingly, 5-LO activity appears to be involved in nuclear retention and inactivation of wild-type p53 in malignant mesothelioma cells. In these cells, genetic or pharmacological inhibition of 5-LO enabled suppression of in vitro tumorigenicity by low doses of chemotherapeutic drugs. Together, these results uncover novel functions of 5-LO and contribute to the understanding of 5-LO involvement in tumor progression. Moreover, they provide a rationale to the therapeutic use of 5-LO inhibitors to enhance cancer chemosensitivity in selected tumors.
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PMID:5-lipoxygenase antagonizes genotoxic stress-induced apoptosis by altering p53 nuclear trafficking. 1537 79

Gliomatosis cerebri (GC) is regarded as a rare glial neoplasm of unknown origin, and a detailed analysis of molecular alterations underlying this disease has started only recently. However, because GC characteristically affects large parts of the brain and spinal cord, the distribution of genetic alterations may be highly variable between different tumor areas. Additionally, tumor areas with varying degrees of differentiation may be present, raising the possibility to model the genetic events associated with astrocytoma progression. Here we analyzed various tumor regions with features of low-grade and high-grade astrocytomas from 9 autopsy-proven GC cases for the immunoexpression of the cell cycle-controlling proteins mdm2, p21, p27/kip1, p16, and Rb. The samples were also screened for EGFR expression, and for amplification of the EGFR and MDM2 genes. Furthermore, allelic losses of the CDKN2A gene and of a PTEN flanking region of chromosome 10 were determined. We detected tumor regions with immunoexpression of p21 only rarely in our series, without association to the tumor grade. No MDM2 gene amplification was detected. In contrast, three cases demonstrated maintained Rb expression. The expression of p27(kip1) showed a clear reduction with increasing astrocytoma malignancy in 7 cases. Allelic loss of the CDKN2A gene occurred in 5 patients but was not related to the tumor grading, nor to the intensity of p16 immunoexpression. No homozygous CDKN2Adeletions were detected. EGFR amplification was also absent in our series, but one case demonstrated EGFR expression only in the high-grade tumor area. Allelic losses on chromosome 10 were found in one out of six informative cases. However, marked differences in the immunoexpression, as well as in the distribution of genetic aberrations were seen between different tumor samples within a given case. The distribution of the alterations suggests that these molecular genetic changes represent secondary events, which may develop within tumor clones derived from a common founder tumor clone characterized by extraordinary spreading through the brain. Moreover, the detected aberrations in gliomatosis cerebri can reflect the tumor progression associated with secondary malignant astrocytoma formation even within a single case.
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PMID:Alterations of cell cycle regulators in gliomatosis cerebri. 1592 90

The tumor suppressor gene, p53, in response to DNA damage/hypoxia, induces growth arrest and/or apoptosis. Inactivation of p53, by mutations and/or overexpression of the mdm2 gene, confers a selective advantage to tumor cells under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its life underground at low-oxygen tensions and hence has developed a wide range of respiratory/molecular adaptations to hypoxic stress. We previously reported that the highly conserved p53 Arg(R)-174 is substituted by lysine (K) in Spalax, identical to a tumor-associated mutation. Functionality assays revealed that Spalax p53 and human R174K-mutated p53 were unable to induce human/Spalax apaf1, an apoptotic target gene, while over-activating the mdm2 gene. Moreover, cells transfected with human p53 underwent more extensive apoptosis (44.8%) as compared to Spalax p53 (23.2%) transfected cells. To support our hypothesis that the pattern of activity in Spalax is related to hypoxia tolerance, we quantified apaf1 and mdm2 mRNA levels under normoxia (21% O(2)), short-acute hypoxic stress (5 h at 6% O(2)) and long-mild hypoxic insult (44 h at 10% O(2)). Results were compared to those of rats under similar conditions. Following hypoxia, Spalax apaf1 mRNA levels decreased significantly, but increased in rats. apip mRNA levels, a negative regulator of apaf1, increased in Spalax and decreased in rats. mdm2 mRNA levels under hypoxia were significantly higher in Spalax. We conclude that, similar to our previous in-vitro work, two parallel hypoxia-adaptive mechanisms evolved in Spalax: mutated p53 and p53 response element leading to a bias against apoptosis and increased mdm2, which are analogous to observations in tumor development.
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PMID:The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors. 2070 75

Many types of human cancers overexpress MDM2 protein. A common characteristic among these cancers is an associated increase in mdm2 splice variants. Provided here is a comprehensive list, based on a literature review, of over 70 mdm2 variants. These variants are grouped according to in-frame versus out-of-frame status and their potential (or ability) to be translated into isoform proteins. We describe the putative functions for these mdm2 splice variant mRNAs, as well as the mechanistic drivers associated with increased mdm2 transcription and splicing. The paradoxical signal transduction functions of the most commonly studied variants mdm2-a,-b and -c are addressed for their outcomes in the presence and absence of wild-type p53. These outcomes vary from tumor promotion to growth arrest. Finally, we present issues in the detection of endogenous MDM2 protein and how many of the antibodies commonly used to detect MDM2 do not present a full picture of the cellular representation of the isoform proteins. This review provides a focusing lens for individuals interested in learning about the complexities of mdm2 mRNAs and their protein isoforms as well as the roles MDM2 isoforms may play in cancer progression.
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PMID:Splice variants of MDM2 in oncogenesis. 2520 Nov 99


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