Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied p53 gene at the DNA and protein level in human gastric cancer tissues and corresponding normal gastric mucosae from 20 cases of patients undergone radical surgery. By Southern blotting, the p53 gene was found to be partially deleted in 30% (6/20) of gastric cancer tissues. ABC immunohistochemical study of p53 expression was carried out on cryostat sections using monoclonal antibodies (PAb 1801) to p53. High level expression of mutated p53 protein was detected in 55% (11/20) gastric cancer tissues. The staining pattern was intranuclear and/or intracytoplamic. There was no detectable staining of any of the normal gastric tissues with 1801 antibody. The positive rate of p53 overexpression was higher in poorly-differenciated glandular carcinomas than well-differenciated cancer (P = 0.0116). Highly significant association exists between high level p53 expression and allele deletion (r = 0.59). The date indicate that inactivation of p53 gene is important in human gastric carcinogenesis and tumor progression. The assay of p53 gene structure and products may provide new biologically relevant tumor marks for predicting the behavior of gastric carcinomas, identifying more aggressive tumors, determining prognosis of the patients and guiding treatment.
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PMID:[p53 gene deletion and abnormal expression in gastric carcinoma]. 765 19

To examine the significance of Y chromosome losses in bladder cancer, fluorescence in situ hybridization (FISH) was used to determine its prevalence and associations with known parameters of malignancy. Cells were dissociated from formalin-fixed paraffin-embedded bladder tumors from 68 male patients and from 11 post-mortem bladder washes of male patients with a negative bladder cancer history, and were examined by FISH using centromeric probes for chromosomes X, Y, 7, 9, and 17. Nullisomy for chromosome Y was seen in 23 of 68 tumors (34%), monosomy in 28 of 68 tumors (41%), and polysomy in 17 of 68 tumors (25%). There was no association between chromosome Y loss and tumor grade, stage, tumor growth fraction (Ki67 LI), p53 immunostaining, and presence of p53 deletions. Patient age was higher for tumors with a Y loss (73.5 +/- 12.0 years) than for tumors without Y loss (66.6 +/- 10.8 years; p = 0.0207). In one normal bladder wash, a distinct subpopulation (38% of cells) with Y nullisomy was seen. These data suggest that Y loss is a frequent event that can occur early in bladder cancer, although there is no evidence for a role of Y loss in tumor progression.
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PMID:Y chromosome loss detected by FISH in bladder cancer. 766 48

Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes (p53, MDM2, Rb, E-cadherin, APC) within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 (PSI, HT1197) in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 (TCCSUP, SCaBER, 5637, HT1376, J82) cell lines. Absence of E-cadherin was recorded in 5/15 cell lines (TCCSUP, EJ, KK47, UM-UC-3, J82) with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression.
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PMID:Human bladder carcinoma cell lines as indicators of oncogenic change relevant to urothelial neoplastic progression. 766 81

Bax is a homologue of Bcl-2 that promotes apoptosis. Bax protein levels were assessed by immunohistochemical methods in primary tumors derived from 119 women with metastatic breast cancer. These patients had received combination chemotherapy either with a once a month dosage schedule or in 4 weekly divided doses. The BAX immunostaining results were retrospectively compared with overall survival, time to tumor progression (TTP), and response, as well as several laboratory markers. Normal breast epithelium and in situ carcinomas immunostained positively for Bax. Marked reductions in Bax immunostaining were observed in 40 (34%) of 119 evaluable tumors. Reduced Bax correlated with shorter overall survival (median, 8.1 versus 15.7 months; P = 0.04), faster TTP (median, 2.0 versus 6.3 months; P = 0.009), and failure to respond (complete response, partial responses; 6% versus 42%, P = 0.01) in the subgroup of patients who received divided dose therapy. Reduced Bax immunostaining was not significant in the monthly dose group. When the two groups were combined, however, reduced Bax was significantly correlated in univariate analysis with failure to respond (21 versus 43% achieving complete response or partial response; P = 0.02), faster TTP (median, 3.7 versus 9.0 months; P = 0.02), and shorter survival (median, 10.7 versus 17.1 months; P = 0.04). Bax immunostaining was not significantly correlated with tumor histology, S-phase fraction, aneuploidy, p53 HER2, or cathepsin D, but was positively associated with Bcl-2 (P = 0.005). In multivariate analysis (Bax, tumor grade, and treatment group), reduced Bax was strongly associated with faster TTP (P approximately equal to 0.009) and shorter survival (P approximately equal to 0.001). Although highly preliminary, the finding suggest that loss of Bax immunostaining represents a novel prognostic indicator of poor response to chemotherapy and shorter survival in women with metastatic breast cancer, and raise the possibility that the subgroup of women with Bax-negative tumors may benefit from more aggressive therapy.
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PMID:Reduced expression of proapoptotic gene BAX is associated with poor response rates to combination chemotherapy and shorter survival in women with metastatic breast adenocarcinoma. 767 Dec 62

Neoplastic diseases are characterized by uncoordinated cell growth. Cellular proliferation follows an orderly progression through the cell cycle, which is governed by protein complexes composed of cyclins and cyclin-dependent kinases. These complexes exert their regulatory function by phosphorylation of key proteins involved in cell cycle transitions, such as the product encoded by the retinoblastoma gene (pRB). Mutations and overexpression of cyclins and cyclin-dependent kinases, mainly cyclin D1 and Cdk4, have been reported and proposed to be oncogenic events. More recently, a new family of negative regulators functioning as Cdk-inhibitory molecules has been identified. Because of their recessive nature in cell cycle control and the fact that some of them are mutated in human tumors, it has been suggested that they may also function as tumor suppressor genes. It appears that the molecular networking of these proteins and complexes impact on two fundamental cell cycle regulators: p53 and pRB. Cross-talk pathways between these two nuclear proteins are being delineated, implying potential links between p53 and pRB in cell cycle control, apoptosis, and tumor progression. In addition, the high rate and mutation pattern of TP53 and RB in primary tumors have rendered them prototype tumor suppressor genes. Furthermore, detection of TP53 and RB mutations and altered expression of their encoded products appear to be of clinical significance, often correlating with prognosis, when identified in specific cancers. Based on these findings, new strategies are being developed in the emerging field of gene replacement-therapy.
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PMID:Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. 767 68

p53 alterations were studied in a group of 22 primary squamous cell carcinomas (SCC) of the head and neck and in 10 cell lines derived from SCC. Positive immunohistochemical detection of p53 was accomplished in 10 of 22 primary tumors and in 7 of 10 SCC cell lines. Loss of heterozygosity of chromosome 17p, were the p53 gene is localized, was seen in five of seven SCC lines studied. DNA sequencing of the p53 gene of these five cell lines that had lost one allele showed p53 mutations in the remaining allele. In addition, from six primary SCC that exhibited loss of heterozygosity of chromosome 17p, three showed missense mutations of the p53 gene. The mutations of primary tumors and SCC cell lines were scattered in the midregion of the gene, affecting codons 151, 155, 174, 194, 220, 248, and 273. Five of these mutations modified guanine residues, a phenomenon that has been associated with the effect of carcinogens contained in tobacco smoke. Collectively these data show that approximately 50% of primary tumors and cell lines derived from SCC of the head and neck showed abnormalities of the p53 gene. In addition, it is of interest to note that the most invasive cell lines, as determined in an in vivo assay using xenotransplantation of tumor cells into denuded rat tracheal grafts, exhibited the most intense staining. Similarly, of five very advanced primary tumors, four showed intense p53 immunostain. These observations support the evidence that alterations in this tumor suppressor gene could be related to late events in tumor progression.
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PMID:p53 alterations in human squamous cell carcinomas and carcinoma cell lines. 768 63

The p53 tumor-suppressor gene encodes a cell-cycle checkpoint protein that functions in the G1 phase of the cell cycle. When DNA damage is incurred, p53 transactivates a number of downstream genes whose products, with diverse biologic activities, each make a contribution to the cellular response to DNA damage. One major p53-mediated stress response is the G1 cell-cycle arrest, or delay, which probably allows the cell time to repair DNA damage prior to S-phase entry. In cells lacking p53 function, which include most cancer cells, a condition of genomic instability results from checkpoint loss that culminates in gene amplifications, aneuploidy, and other chromosomal aberrations. These abnormalities contribute to the clonal evolution of cancer cells and tumor progression. The role of p53 in radioresistance and chemoresistance is discussed.
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PMID:Genomic instability and the role of p53 mutations in cancer cells. 769 66

Inappropriate expression of Met, the receptor for hepatocyte growth factor/scatter factor, has been implicated in sarcomagenesis via an autocrine mechanism. Sarcomas occur at high frequency in individuals with Li-Fraumeni syndrome as well as in p53-deficient mice. Here we show that these tumors express high levels of Met. Moreover, late passage fibroblast cell lines established from p53-deficient animals overexpress Met and can be tumorigenic in athymic nude mice, suggesting that progression occurs in vitro. The tumor explants display increased hepatocyte growth factor/scatter factor expression and Met turnover, indicating that autocrine Met activation contributes to tumor progression. Thus, the loss of wild-type p53 appears to greatly enhance the opportunity for inappropriate Met expression. Loss of p53 function does not by itself cause transformation, but inappropriate Met expression may be an important factor in sarcomagenesis.
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PMID:Met proto-oncogene product is overexpressed in tumors of p53-deficient mice and tumors of Li-Fraumeni patients. 772 66

The most common tumor suppressor genes involved in the prediction of bladder tumor progression are the Rb and the p53 genes. This article summarizes current data on the use of these markers in prognostic evaluation.
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PMID:Tumor suppressor gene alterations in bladder carcinoma. Translational correlates to clinical practice. 779 83

The p53 gene product is required for activation of an apoptotic pathway triggered by oncogenes and cytotoxic agents. Wilms' tumor, a pediatric renal malignancy, provides a paradigm for evaluating genetic events involved in tumor progression. This malignancy is generally not associated with p53 mutations, and even in advanced disease states is quite responsive to current treatment regimens. The anaplastic histological variant of Wilms' tumor, however, is frequently associated with p53 gene mutations and shows poor prognosis. We analyzed seven Wilms' tumors for which we had paired samples from nonanaplastic and anaplastic regions. p53 mutations were detected in six of these tumors, five of which demonstrated mutations restricted to anaplastic regions. Nonanaplastic cells of the sixth sample were heterozygous for a p53 mutation, whereas the anaplastic area of this tumor showed reduction to homozygosity. These results indicate that progression to anaplasia is associated with clonal expansion of cells which have acquired a p53 mutation. We demonstrated that tumor cells with p53 mutations show attenuated apoptosis, suggesting that such lesions may provide a selective advantage in vivo by decreasing cell death.
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PMID:Clonal expansion and attenuated apoptosis in Wilms' tumors are associated with p53 gene mutations. 781 46


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