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

The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.
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PMID:Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. 935 90

A potentially rate-limiting step in cancer progression is the conversion of a normal human cell into one capable of indefinite proliferation. There are at least two different cellular mechanisms that must be overcome before immortalization occurs. The first step generally requires inactivation of the pathways involving two tumor-suppressor genes, p53 and pRB, and the second step almost always involves the reactivation of the ribonucleoprotein enzyme telomerase. Telomerase synthesizes hexameric repeats (TTAGGG) onto telomeric ends, thereby compensating for telomeric losses that in its absence occurs at each cell division. Telomerase is present in human embryonic tissues, is not detected in most adult tissues, but is upregulated or reactivated in almost 90% of all human cancers. In the present article, I review the telomere-telomerase theory of aging and cancer including the roles of telomerase during human development, in differentiation, and in cancer. Research into the regulation of this enzyme may lead to methods to facilitate the accurate diagnosis of cancer and to the development of novel antitelomerase cancer therapeutics.
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PMID:Telomerase in human development and cancer. 936 34

Only limited data are available on chromosomes specifically involved in the multistep tumorigenesis of prostate cancer. To investigate the cytogenetic status at different stages of prostatic tumor development, we have applied interphase in situ hybridization (ISH) with a set of (peri) centromeric DNA probes--specific for chromosomes 1, 7, 8, and Y--to routinely processed tissue sections of prostatic specimens from 75 different individuals. Our panel consisted of: 16 normal/benign prostatic hyperplasia specimens; 23 primary, localized, prostatic tumors (N0M0 stage); 20 regional lymph node metastases (M0 stage); and 16 distant metastases. Numerical aberrations of at least one chromosome were not observed in normal/benign prostatic hyperplasia cases, but were present in localized tumors (39%), regional lymph node metastases (40%), and distant metastases (69%). Within the different pTNM groups, we observed the following aberrations (listed, within each series, in decreasing order of frequency): -Y, +8, -8, +7 in primary tumors; +8, +7, -Y, +Y, -8 in regional lymph node metastases; and +8, +7, +1, -Y, -8 in distant metastases. In primary tumors, the number of aberrant cases increased significantly with local tumor stage (p < 0.05). A significant increase in gain of chromosome 8 was also observed (p < 0.02). Gain of chromosome 7 and/or 8 showed a significant increase with progression of local tumor stage (p < 0.02). Specific involvement of chromosome 8 was seen in bone metastases, but not in hematogenous metastases to other sites (p = 0.02). Comparative genomic hybridization analysis of these bone metastases disclosed centromere 8 gains as amplifications of the (whole) 8q arm, whereas centromeric loss appeared to be due to loss of 8p sequences. With progression toward metastatic disease, an accumulation of genetic changes was seen as exemplified by gain of chromosome 1, which was solely observed in distant metastases. With tumor progression, gain of chromosomes 7 and/or 8 significantly increased (p = 0.03), whereas the number of cases with aberrations of the Y chromosome did not change. Furthermore, ploidy status determined by ISH revealed a significant increase in the number of aneuploid cases along with advancement of pTNM stage (p = 0.04). Collectively, the data strongly suggest that: (a) gain of chromosome 7 and/or 8 sequences is implicated in prostatic tumor progression; (b) gain of chromosome 8 sequences is related to local tumor growth; (c) overrepresentation of 8q sequences, most likely by isochromosome 8q formation, is involved in metastatic spread to the bone; and (d) changes in the centromeric copy number, as detected by interphase ISH, might in some cases represent structural alterations, such as an isochromosome.
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PMID:Interphase cytogenetics of prostatic tumor progression: specific chromosomal abnormalities are involved in metastasis to the bone. 938 87

Telomerase activity was examined by telomeric repeat amplification protocol assay in thyroid disease states, including adenomas and carcinomas, and correlated with clinicopathological features. Of a total of 26 papillary carcinomas, 16 cases (61.5%) were positive, with the poorly differentiated subtype being predominant (P < 0.05). A significantly more shortened terminal restriction fragment length (P < 0.05), higher incidence of extrathyroidal extension (P < 0.001), and more elevated Ki-67 labeling indices (P < 0.002) were also found in telomerase-positive than in telomerase-negative papillary carcinomas. Of four follicular carcinomas, 3 cases (75.0%) were positive. Positive telomerase activity in follicular adenomas (9/23 cases, 39.1%) and lymphocytic thyroiditis (12/22 cases, 54.5%) appeared to be mainly caused by infiltrating lymphocytes. However, three cases of atypical adenoma with relatively increased Ki-67 labeling indices were positive, suggesting a possibility of malignant potential. The good correlations with extrathyroidal invasiveness, Ki-67 labeling indices and poor differentiation of papillary carcinomas, established by multivariate analysis, suggest that this parameter might have potential application in the estimation of tumor progression and prognosis, and in clinical management.
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PMID:Significant correlation of telomerase activity in thyroid papillary carcinomas with cell differentiation, proliferation and extrathyroidal extension. 941 58

Telomerase activity has been detected in a broad range of human cancers and its expression could be an important step in tumor progression. Here, telomerase activity by the telomeric repeat amplification protocol in cases of benign endometrium, endometrial hyperplasia, and endometrial adenocarcinoma was tested. Telomerase expression was detected in 13 of 14 cases of proliferative phase endometrium, in 7 of 12 cases of secretory phase endometrium, but was not detected in any of 7 cases of atrophic endometrium. Three of three cases with evidence of luteal phase defect and one of four cases of chronic endometritis also expressed telomerase activity. Hyperplastic endometrium was positive for telomerase in 13 of 17 cases. Telomerase activity was detected in 40 of 48 cases of endometrial adenocarcinoma, which included 36 of 43 cases of endometrioid adenocarcinoma and four of five cases of papillary serous carcinoma. The detection of telomerase in endometrial adenocarcinoma was not associated with either architectural grade, myometrial invasion, or stage. There was statistically significant association, however, between telomerase activity in benign atrophic endometrium versus any endometrial abnormality in women 52 years of age or older.
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PMID:Telomerase expression in normal endometrium, endometrial hyperplasia, and endometrial adenocarcinoma. 942 Oct 87

Because telomerase activity is necessary for cell immortality and probably associated with tumor progression, we have evaluated a possible aid for quantitation of the activity to predict intrahepatic recurrences after surgery in patients with hepatocellular carcinoma (HCC). HCC tissues obtained by surgical resection from 20 patients were studied. Telomerase activity was expressed as peaks with a periodicity through a fluorescence-based telomeric repeat amplification protocol using an autosequencer, and the quantity of activity was calculated from peak areas. A ratio of fluorescence intensity depending on telomerase to that of an internal standard was used as a value of relative telomerase activity (RTA). RTA in serially diluted S100 extracts from HepG2 cells was well correlated with the amount of the extracts. The mean RTA value of 36.4 +/- 27.8 (mean +/- SD, 3.21 to 105) in 9 patients suffering from early recurrences after surgery was significantly higher than that (9.84 +/- 7.65; mean +/- SD, 3.00 to 29.0) in 11 patients without intrahepatic recurrences during the early period (P = .004). These results indicate that RTA value can be a useful predictor for intrahepatic recurrences during the early period after surgical resection of HCC.
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PMID:Quantitation of telomerase activity in hepatocellular carcinoma: a possible aid for a prediction of recurrent diseases in the remnant liver. 946 37

Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or "jumping translocations" of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.
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PMID:Jumping translocations of chromosome 1q in multiple myeloma: evidence for a mechanism involving decondensation of pericentromeric heterochromatin. 947 40

The expression of telomerase, the enzyme that synthesizes telomeric DNA de novo, is suppressed in normal somatic human cells but is reactivated during tumorigenesis. This reactivation appears to arrest the normal loss of telomeric DNA incurred as human cells divide. Since continual loss of telomeric DNA is predicted to eventually limit cell proliferation, activation of telomerase in cancer cells may represent an important step in the acquisition of the cell immortalization which occurs during tumor progression. The telomerase holoenzyme is composed of both RNA and protein subunits. In humans, mRNA expression of hTERT (hEST2), the candidate telomerase catalytic subunit gene, appears to parallel the levels of telomerase enzyme activity, suggesting that induction of hTERT is necessary and perhaps sufficient for expression of telomerase activity in tumor cells. To test this model directly, we ectopically expressed an epitope-tagged version of hTERT in telomerase-negative cells and show that telomerase activity was induced to levels comparable to those seen in immortal telomerase-positive cells and that the expressed hTERT protein was physically associated with the cellular telomerase activity. We conclude that synthesis of the hTERT telomerase subunit represents the rate-limiting determinant of telomerase activity in these cells and that this protein, once expressed, becomes part of the functional telomerase holoenzyme.
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PMID:Telomerase activity is restored in human cells by ectopic expression of hTERT (hEST2), the catalytic subunit of telomerase. 952 64

Telomeric length dynamics are thought to play an important role both in the processes of cellular aging and cancer progression. We have revised the primed in situ (PRINS) labeling technique to allow an estimation of the relative length of individual telomeres. We illustrate the applicability of the approach by demonstrating different telomeric sizes not only between blood lymphocytes from a young and an old donor, but also among bone marrow cells from hematological cancer patients. In the latter case we found general variations in telomeric sizes as well as individual telomeric variations that would have escaped detection by other methods. An interesting finding was the selective expansion of a single telomere within a specific subset of cells.
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PMID:Improved detection and comparative sizing of human chromosomal telomeres in situ. 963 58

Telomerase is a ribonucleoprotein that synthesizes tandem arrays of the hexameric DNA sequence TTAGGG at chromosome termini using its RNA component as a template. As most normal cells lack telomerase activity, a progressive shortening of chromosome length occurs with each cell division because of incomplete DNA replication. Cell senescence ensues when a critical telomere length is reached, but importantly, senescence bypass and life span extension occur in normal cells transfected with functional telomerase activity. Almost 90% of all tumors express telomerase activity, implying that telomerase is an important determinant in tumor progression and cell immortalization. However, the exact role and regulation of the individual components of the telomerase complex are not fully understood and would benefit from the availability of specific inhibitors. In this study, we investigated the potential use of chemically stabilized, catalytic RNA molecules (hammerhead ribozymes) to inhibit telomerase activity by cleaving the RNA component in a sequence-specific manner. Catalytically competent (active) hammerhead ribozymes containing 2'-O-methyl ribonucleotides for enhanced biologic stability and designed to be complementary to the RNA component of human telomerase exhibited dose-dependent inhibition of telomerase activity in human glioma U87-MG cell lysates with an IC50 of around 0.4 microM. Catalytically incompetent (inactive) ribozymes or mismatched ribozymes with reduced hybridization capability to telomerase RNA did not inhibit telomerase activity, as detected by a PCR-based telomeric repeat amplification protocol (TRAP) assay. In vitro cleavage reactions using short substrates and RT-PCR analyses of the full-length RNA substrate in U87-MG cell lysates confirmed a sequence-specific catalytic cleavage of the targeted RNA component of telomerase. Exogenously administrable, synthetic ribozymes may have important uses in further understanding the role and regulation of this ribonucleoprotein in normal and diseased tissues as well as in the potential therapy of telomerase-positive tumors.
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PMID:Synthetic 2'-O-methyl-modified hammerhead ribozymes targeted to the RNA component of telomerase as sequence-specific inhibitors of telomerase activity. 974 68


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