Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Comparative genomic hybridization was used to map copy number abnormalities in 48 short-term cell cultures established from different stages and types of human melanoma. A variety of random and non-random chromosomal alterations were detected, with gains within chromosomes 20q, 7q, 7p, 20p, 6p and 17q and losses in 9p, 10q, 6q, 10p, 4q, and 11q being the most common observations. In addition, several other chromosomal loci were over- or under-represented in subgroups of melanomas. For example, sequences on 3q26 were over-represented in 33% and on 5p15.33 in 27% of cell cultures, reaching the level of amplification in 12% and 22%, respectively. These regions harbour the two essential genes for the enzyme telomerase: the telomerase reverse transcriptase gene (hTERT) on 5p15.33 and the telomerase RNA component gene (hTERC) on 3q26. Using fluorescence in situ hybridization and Southern blot analysis, both genes were shown to be over-represented or amplified in several melanomas. Interestingly, hTERT amplification was abundant in superficial spreading primary melanomas, subcutaneous metastases and malignant effusion-derived cells, but completely absent or very rare in primary nodular melanomas as well as brain, bone and lymph node metastases. Several chromosomes or chromosomal regions harbouring telomerase-suppressing activities (3p, 4, 6 and 10p) were frequently under-represented in melanomas. Our data suggest that genetic alterations at several chromosomal loci might facilitate activation of telomerase during the development of cutaneous malignant melanoma.
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PMID:Chromosomal imbalances in primary and metastatic melanomas: over-representation of essential telomerase genes. 1451 90

In a search for molecular markers providing both informative diagnostics of malignant disease, and rational stratification of a therapeutic strategy to achieve optimal response in a given patient, we examined the possibility of using telomerase for this purpose in colorectal cancer. Telomerase, a ribonucleoprotein enzyme complex catalysing synthesis of chromosome ends (telomeres), has been known as an almost universal tumor marker but its predictive value has been found in only a limited number of malignant tumor types. Telomerase activity and expression of its catalytic subunit hTERT was determined in 82 surgical specimens from 41 patients (a sample of tumor tissue and of adjacent morphologically normal tissue was obtained from each patient). Telomerase activity was present in tumor samples from 34 (83%) patients, reaching an average value of 47.6 telomerase units (T.U.), while adjacent tissue specimens were either negative (in 25 (61%) patients), or slightly positive (in 16 (39%) patients) showing 1.5 T.U. on average. In tumor samples from patients without lymphatic node metastases (pN0), an average of 37.1 T.U was found. In contrast, in tumor samples from patients with lymphatic node involvement (pN1 or pN2) the average activity was significantly higher (60.2 T.U., p<0.05). In patients with distant metastases a tendency towards higher telomerase activity, although lacking statistical significance, could be observed. Among patients that obtained chemotherapy with 5-fluoruracil, those with low telomerase activity showed a tendency to chemosensitivity. Expression of hTERT was detected not only in samples showing telomerase activity, but also in a considerable portion of telomerase-negative samples either from the tumor or the adjacent normal tissue. We demonstrate that some of these apparent discrepancies may be attributed to differential splicing of hTERT mRNA. We conclude that TRAP assay for telomerase activity is more informative than the common testing for hTERT expression. Telomerase activity is useful both as a diagnostic as well as a predictive factor in colorectal cancer.
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PMID:Telomerase as a diagnostic and predictive marker in colorectal carcinoma. 1519 Apr 17

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.
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PMID:Colon cancer: genomics and apoptotic events. 1525 76

In the present study, the telomerase activity and the putative alterations of genes involved in cell-cycle control (p53, Fas and pRb) were investigated in a radiation-induced meningioma with multiple recurrences and pleural-pulmonary metastases (the patient, a 34-year-old male, had a history of carcinoma of the tongue of testicular lymphocytic lymphoma). Expression of VEGF and vasculature pattern were also studied. Expression of VEGF, pRb and p53 were evaluated by immunohistochemistry on formalin-fixed, paraffin-embedded samples of the tumor. VEGFmRNA was determined by competitive PCR. Fas, FasL and hTERT were evaluated by RT-PCR. Telomerase activity was examined by the TRAP assay. An intense vascularization was observed, supported by high expression of VEGFmRNA (isoforms 121 and 165). pRb and p53 were overexpressed. Fas was undetectable with PCR, whereas FasL was positive. Furthermore, the lesion showed an elevated telomerase activity (TPG, 22), according to the high expression of hTERT. These findings emphasized that even among generally benign neoplasms, such as meningiomas, some highly malignant tumors may develop, as in our case, in which several mechanisms were activated in the cancer progression to guarantee the immortalization of cellular clones (angiogenic phenomenon, activation of telomerase and of anti-apoptotic mechanisms) and the blood spread. Thus, the data illustrate the importance of searching for genetic aberrations (which are a hallmark of malignancy) in meningiomas, as predictive and reliable factors of the possibility to recur and to metastasize.
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PMID:Immunohistochemical and molecular study of radiation-induced multiple meningiomas with pleural and pulmonary metastasis. 1531 14

The systemic delivery of genetic therapies required for the treatment of inaccessible tumors and metastases remains a challenge despite the development of various viral and synthetic vector systems. Here we show that a synthetic vector system based on polypropylenimine dendrimers has the desired properties of a systemic delivery vehicle and mediates efficient transgene expression in tumors after i.v. administration. The systemic tumor necrosis factor alpha (TNFalpha) gene therapy was efficacious in the experimental treatment of established A431 epidermoid carcinoma, C33a cervix carcinoma, and LS174T colorectal adenocarcinoma. Specifically, the systemic injection of dendrimer nanoparticles containing a TNFalpha expression plasmid regulated by telomerase gene promoters (hTR and hTERT) leads to transgene expression, regression of remote xenograft murine tumors, and long-term survival of up to 100% of the animals. Interestingly, these dendrimers and, to a lesser extent, other common polymeric transfection agents also exhibit plasmid-independent antitumor activity, ranging from pronounced growth retardation to complete tumor regression. The genetic therapy as well as treatment with dendrimer alone was well tolerated with no apparent signs of toxicity in the animals. The combination of intrinsic dendrimer activity and transcriptionally targeted TNFalpha when complexed was significantly more potent than either treatment alone or when both were administered in sequence. The combination of pharmacologically active synthetic transfection agent and transcriptionally targeted antitumor gene creates an efficacious gene medicine for the systemic treatment of experimental solid tumors.
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PMID:Synthetic anticancer gene medicine exploits intrinsic antitumor activity of cationic vector to cure established tumors. 1616 79

There is increased staining of endothelins (ET-1, -2, and -3) and receptors (ET-RA and -RB) in invasive breast tumors compared to nonneoplastic tissue, and ETs stimulate MCF-7 cell invasion in vitro. We analyzed ETstimulation of benign and transformed mammary epithelial cells, and whether expression of ETs is sufficient to induce invasiveness. In breast cancer patient serum, ET-1 was increased in those patients with lymph node metastases compared to those with no lymph node involvement; ETs, however, had no mitogenic effect on breast tumor cell lines in vitro. The benign mammary epithelial cell line, hTERT-HME1, and the poorly invasive breast tumor cell line MCF-7 secreted low levels of ET-1, while the invasive cell lines SKBR3 and MDAMB231 secreted high levels. Expression of the ETs and receptors by the cell lines broadly correlated with their in vitro invasiveness; overexpression of ETs in MCF-7 cells increased basal invasion. ET-mediated invasion involved both receptors and a calcium influx to induce a pertussis toxin-sensitive MAPK pathway. MMP-14 activity was induced via ET-RA in an autocrine manner. In contrast to transformed cells, ET stimulation or overexpression did not induce an invasive phenotype in benign cells. Benign cells do not respond to ETs, and ET expression is not sufficient to induce invasion; however, the level of ET production by tumor cells correlates with their invasiveness, and increasing expression of the ET axis promotes breast tumor cell invasion via both receptors, while MMP-14 is induced via ET-RA.
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PMID:Expression of endothelins and their receptors promotes an invasive phenotype of breast tumor cells but is insufficient to induce invasion in benign cells. 1627 97

A pheochromocytoma is a neoplasm composed of cells which synthesize and release catecholamines. These tumors produce the hypertension which can be cured with surgical excision of the lesion. The pathological picture of pheochromocytomas is varied and nothing but the presence of metastases can determine aggressiveness of this neoplasm. Current studies try to look for other biological markers which can separate malignant tumors before they metastasize. It allows to target with more effective therapy. Many studies analyze details of microscopic features of these tumors, immunohistochemical markers and molecular disorders. It seems that the most important factor in estimation of aggressiveness of pheochromocytomas is PASS scale. The detection of high expression of telomerase and hTERT and high proliferative activity, measured by immunohistochemistry with the MIB-1 antibody supports most strongly biological malignancy of pheochromocytoma.
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PMID:[Markers of malignancy in pheochromocytomas]. 1682 Dec 16

Giant cell tumour of bone (GCTB) is a benign bone tumour known for the unpredictable clinical behaviour of recurrences and, in rare instances, distant metastases. It consists of uniformly distributed osteoclastic giant cells in a background of mononuclear rounded and spindle-shaped cells. Cytogenetically, telomeric associations are the most common chromosomal aberrations, which, however, are normally almost exclusively found in high-grade malignancies. GCTB has often been regarded as a polyclonal tumour, but more recently a recurrent specific aberration was reported, which suggests a possible role for disturbed telomere maintenance. Here we further investigate telomere maintenance in GCTB using 19 samples from 19 patients. A combination of immunofluorescence and FISH was performed, applying antibodies directed against promyelocytic leukaemia body-related antigen and hTERT and using telomere peptide nucleic acid probes. The TRAP assay and telomere restriction fragment length analysis were performed for functional detection of telomerase activity and alternative telomere lengthening. Both osteoclastic giant cells and mononuclear cells showed positivity for hTERT and promyelocytic leukaemia body-related antigen. In most mononuclear cells, co-expression was present. The TRAP assay demonstrated heterogeneous telomerase activity, while telomere restriction fragment length analysis showed non-heterogeneous telomere lengths, indicating the absence of alternative telomere lengthening. Confocal microscopy showed stereometric co-localization of nucleolin with promyelocytic leukaemia body-related antigen in association with telomeres in the spindle-shaped cells. hTERT was more diffusely distributed throughout the nucleus. Our results show that GCTB demonstrates remarkable telomere maintenance of activated telomerase and inactivated alternative telomere lengthening in the presence of normal mean telomere restriction fragment lengths. These findings strongly suggest that these aggregates, while activating telomerase, are part of a structural telomere protective-capping mechanism rather than of a telomere-lengthening mechanism. Telomere maintenance could be considered an important key factor in the pathogenesis of GCTB.
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PMID:Telomere biology in giant cell tumour of bone. 1827 85

The hTERT gene encodes the telomerase catalytic subunit that plays a key role in cancer cell immortalization. Earlier, hTERT amplification was detected in squamous cell cervical carcinomas (SCC), however possible relations between elevated hTERT mRNA level and gene amplification was not studied. Here, we compared the hTERT expression and copy number in the same tumors by quantitative real-time PCR. The hTERT DNA copy number was virtually unchanged in all 33 studied tumors, when compared to normal tissues. This result was confirmed using two reference genes beta-actin and beta-D-glucuronidase. Nevertheless, the activation of hTERT expression was found in 80% of cases (37/46, p<0.001). There was no correlation between the degree of mRNA increase and the tumor size and/or presence of metastases. No hTERT gene expression was observed in 20% of cases (9/46), while the control GADPH expression was unchanged. The detected elevation of the hTERT mRNA level was found using primers specific to functionally active full-length isoform of mRNA. Similar results were obtained with SCC cell lines carrying human papilloma virus (HPV) genomes. We conclude that frequent activation of hTERT expression in SCC is not associated with gene amplification.
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PMID:Activation of the hTERT expression in squamous cell cervical carcinoma is not associated with gene amplification. 1863 13

Telomelysin is a telomerase-specific replication-competent adenovirus with telomerase reverse transcriptase (hTERT) promoter, which has shown strong anti-tumor effects on a variety of human cancer cells. Human head and neck squamous cell carcinoma (HNSCC) cell lines and a murine HNSCC (NR-S1) model were used to investigate whether telomelysin (OBP-301) had a therapeutic efficacy for HNSCC. We examined the cell killing effects of telomelysin and the induction of tumor cell apoptosis by telomelysin in vitro. Based on these data, we examined whether telomelysin therapy produced therapeutic benefits in vivo. The results demonstrated that the treatment of telomelysin led to significant tumor regression on the side with subcutaneous NR-S1 tumor. We first confirmed the direct anti-tumor effect of intratumoral telomelysin injections in a murine HNSCC model. Further analyses of the augmented anti-tumor effects revealed that telomelysin increased the source of tumor antigens for immune cells, resulting in the induction of CD4+ and CD8+ T cells responsible for the in vivo tumor regression of treated and untreated tumors. Subsequently, an elevated IFN-gamma production of spleen cells was observed in mice treated with telomelysin. These results raise the possibility that telomelysin enhances the immune response in addition to its direct tumor cell killing activity. These findings suggest that telomelysin is a potent agent for the treatment of HNSCC patients with multiple metastases.
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PMID:Anti-tumor effects of telomelysin for head and neck squamous cell carcinoma. 1902 Jul 15


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