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Saeed H, Iqtedar M. Stem cell function and maintenance - ends that matter: role of telomeres and telomerase. J Biosci 2014; 38:641-9. [PMID: 23938394 DOI: 10.1007/s12038-013-9346-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/ organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive agerelated degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon.
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Affiliation(s)
- Hamid Saeed
- Department of Endocrinology, School of Medicine, Stanford University, Stanford, CA, USA.
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Lü MH, Deng JQ, Cao YL, Fang DC, Zhang Y, Yang SM. Prognostic role of telomerase activity in gastric adenocarcinoma: A meta-analysis. Exp Ther Med 2012; 3:728-734. [PMID: 22969960 DOI: 10.3892/etm.2012.471] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 01/13/2012] [Indexed: 02/07/2023] Open
Abstract
Activation of telomerase is involved in carcinogenesis in most types of cancers. However, the prognostic value of telomerase activity (TA) in patients with gastric carcinoma (GC) remains controversial. We conducted a meta-analysis to assess the relationship between TA and the clinical outcome of GC. A meta-analysis of 18 studies (886 patients) was performed to evaluate the association between TA and metastasis-related parameters in GC patients by searching databases, including PubMed, MEDLINE, EMBASE, Web of Science databases, Cochrane Library and the Chinese Biomedical Literature database (CBM) (last search updated in October 2011). We used the odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between TA and metastasis of GC. Our analysis results indicated that high telomerase activity expression tended to be associated with the presence of lymph node metastasis (866 patients) (OR=2.03, 95% CI 1.21-3.39, p=0.007), the depth of invasion (886 patients) (OR=1.87, 95% CI 1.30-2.70, p=0.0007), distant metastasis (407 patients) (OR=2.71, 95% CI 1.59-4.63, p=0.0002), tumor size (466 patients) (OR=2.14, 95% CI 1.31-3.50, p=0.002) and TNM stage (711 patients) (OR=2.39, 95% CI 1.30-4.41, p=0.005). However, high TA expression was not associated with the presence of histologic differentiation (791 patients) (OR=1.51, 95% CI 0.73-3.11, p=0.26). In conclusion, telomerase overexpression not only plays a key role in primary initiation, but also promotes invasion and metastatic progression of GC. These findings raise the possibility of using TA to screen for the prognosis of gastric cancer.
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Affiliation(s)
- Mu-Han Lü
- Institute of Gastroenterology, Southwest Hospital, Third Military Medical University
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3
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Chen CH, Chen RJ. Prevalence of telomerase activity in human cancer. J Formos Med Assoc 2011; 110:275-89. [PMID: 21621148 DOI: 10.1016/s0929-6646(11)60043-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 10/30/2010] [Accepted: 12/01/2010] [Indexed: 12/13/2022] Open
Abstract
Telomerase activity has been measured in a wide variety of cancerous and non-cancerous tissue types, and the vast majority of clinical studies have shown a direct correlation between it and the presence of cancerous cells. Telomerase plays a key role in cellular immortality and tumorigenesis. Telomerase is activated in 80-90% of human carcinomas, but not in normal somatic cells, therefore, its detection holds promise as a diagnostic marker for cancer. Measurable levels of telomerase have been detected in malignant cells from various samples: tissue from gestational trophoblastic neoplasms; squamous carcinoma cells from oral rinses; lung carcinoma cells from bronchial washings; colorectal carcinoma cells from colonic luminal washings; bladder carcinoma cells from urine or bladder washings; and breast carcinoma or thyroid cancer cells from fine needle aspirations. Such clinical tests for telomerase can be useful as non-invasive and cost-effective methods for early detection and monitoring of cancer. In addition, telomerase activity has been shown to correlate with poor clinical outcome in late-stage diseases such as non-small cell lung cancer, colorectal cancer, and soft tissue sarcomas. In such cases, testing for telomerase activity can be used to identify patients with a poor prognosis and to select those who might benefit from adjuvant treatment. Our review of the latest medical advances in this field reveals that telomerase holds great promise as a biomarker for early cancer detection and monitoring, and has considerable potential as the basis for developing new anticancer therapies.
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Affiliation(s)
- Chi-Hau Chen
- Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
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4
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Hiyama E, Hiyama K. Telomerase detection in the diagnosis and prognosis of cancer. Cytotechnology 2011; 45:61-74. [PMID: 19003244 DOI: 10.1007/s10616-004-5126-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2004] [Accepted: 09/21/2004] [Indexed: 01/27/2023] Open
Abstract
Telomerase, a critical enzyme responsible 'for cellular immortality, is usually repressed in somatic cells except for lymphocytes and self-renewal cells, but is activated in approximately 85% of human cancer tissues. The human telomerase reverse transcriptase (hTERT) is the catalytic component of human telomerase. In cancers in which telomerase activation occurs at the early stages of the disease, telomerase activity and hTERT expression are useful markers for the detection of cancer cells. In other cancers in which telomerase becomes upregulated upon tumor progression, they are useful as prognostic indicators. However, careful attention should be paid to false-negative results caused by the instability of telomerase and of the hTERT mRNA and the presence of PCR inhibitors, as well as to false-positive results caused by the presence of alternatively spliced hTERT mRNA and normal cells with telomerase activity. Recently, methods for the in situ detection of the hTERT mRNA and protein have been developed. These methods should facilitate the unequivocal detection of cancer cells, even in tissues containing a background of normal telomerase-positive cells.
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Affiliation(s)
- Eiso Hiyama
- Natural Science Center for Basic Research and Development, RIRBM, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan,
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Hu X, Wu H, Zhang S, Yuan H, Cao L. Clinical Significance of Telomerase Activity in Gastric Carcinoma and Peritoneal Dissemination. J Int Med Res 2009; 37:1127-38. [PMID: 19761695 DOI: 10.1177/147323000903700417] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Telomerase activity is responsible for telomere maintenance and is believed to be crucial in most cancer cells, but its significance in gastric cancer remains unknown. This observational study investigated whether there is a relationship between telomerase activity and the development of gastric cancer, and between telomerase activity and peritoneal dissemination. Telomerase activity was measured in primary gastric cancers and in peritoneal washings from the same patients, and findings were compared with those of conventional cytology and an immunoassay for cancer antigen 125 (CA125). Positive cytological examination and telomerase activity in peritoneal washings both correlated with the histological grade, depth of tumour invasion, area of serosal invasion and peritoneal metastasis. The detection of free cancer cells in peritoneal washings by the telomeric repeat amplification protocol/enzyme-linked immunosorbent assay (TRAP–ELISA) was significantly more sensitive than cytology or the CA125 immunoassay, suggesting that this could be used to diagnose early peritoneal dissemination.
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Affiliation(s)
- X Hu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - H Wu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - S Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - H Yuan
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - L Cao
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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Proctor A, Brownhill SC, Burchill SA. The promise of telomere length, telomerase activity and its regulation in the translocation-dependent cancer ESFT; clinical challenges and utility. Biochim Biophys Acta Mol Basis Dis 2009; 1792:260-74. [PMID: 19264125 DOI: 10.1016/j.bbadis.2009.02.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2009] [Revised: 02/19/2009] [Accepted: 02/20/2009] [Indexed: 01/12/2023]
Abstract
The Ewing's sarcoma family of tumours (ESFT) are diagnosed by EWS-ETS gene translocations. The resulting fusion proteins play a role in both the initiation and maintenance of these solid aggressive malignant tumours, suppressing cellular senescence and increasing cell proliferation and survival. EWS-ETS fusion proteins have altered transcriptional activity, inducing expression of a number of different target genes including telomerase. Up-regulation of hTERT is most likely responsible for the high levels of telomerase activity in primary ESFT, although telomerase activity and expression of hTERT are not predictive of outcome. However levels of telomerase activity in peripheral blood may be useful to monitor response to some therapeutics. Despite high levels of telomerase activity, telomeres in ESFT are frequently shorter than those of matched normal cells. Uncertainty about the role that telomerase and regulators of its activity play in the maintenance of telomere length in normal and cancer cells, and lack of studies examining the relationship between telomerase activity, regulators of its activity and their clinical significance in patient samples have limited their introduction into clinical practice. Studies in clinical samples using standardised assays are critical to establish how telomerase and regulators of its activity might best be exploited for patient benefit.
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Affiliation(s)
- Andrew Proctor
- Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK
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Zachos I, Konstantinopoulos PA, Vandoros GP, Karamouzis MV, Papatsoris AG, Podimatas T, Papachristodoulou A, Chrisofos M, Deliveliotis C, Papavassiliou AG. Predictive value of telomerase reverse transcriptase expression in patients with high risk superficial bladder cancer treated with adjuvant BCG immunotherapy. J Cancer Res Clin Oncol 2009; 135:1169-75. [PMID: 19214569 DOI: 10.1007/s00432-009-0557-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Accepted: 01/26/2009] [Indexed: 10/21/2022]
Abstract
PURPOSE We conducted a prospective study to determine whether expression of telomerase reverse transcriptase (hTERT) is associated with recurrence-free-survival (RFS) or development of invasive disease in patients with high risk superficial bladder cancer (SBC) that received adjuvant BCG immunotherapy. METHODS Thirty patients with high-grade T1 tumors were evaluated. Pre-BCG TURBT and post-BCG specimens were analyzed for hTERT nucleolar expression by immunohistochemistry. RESULTS Post-BCG hTERT expression was statistically significantly lower than pre-BCG hTERT expression. Pre-BCG hTERT nucleolar staining in more than 75% of cells was associated with worse RFS (9 months vs. not yet reached, P = 0.05), while post-BCG hTERT nucleolar staining in more than 50% of the cells was associated with worse RFS (6 months vs. not yet reached, P = 0.001) and development of invasive disease. In multivariate analysis, post-BCG hTERT expression was independently associated with RFS and development of invasive disease. CONCLUSIONS Immunohistochemical evaluation of hTERT may help define a subset of high risk SBC patients that will eventually fail BCG and may therefore benefit from early salvage cystectomy.
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Affiliation(s)
- Ioannis Zachos
- Department of Urology, University of Thessalia, Larissa, Greece
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8
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Wang Q, Kou YW. Study of the expressions of p53 and bcl-2 genes, the telomerase activity and apoptosis in GIST patients. World J Gastroenterol 2007; 13:2626-8. [PMID: 17552015 PMCID: PMC4146828 DOI: 10.3748/wjg.v13.i18.2626] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the relationship between clinicobiological behavior and the expression levels of telomerase activity, apoptosis, p53 gene and bcl-2 gene in gastrointestinal stromal tumors (GISTs).
METHODS: The intensity of telomerase activity, apoptosis, p53 and bcl-2 expression in GISTs were detected by telomeric repeat amplification protocol, in situ end-labeling technique, and immunohistochemistry, respectively.
RESULTS: The positive rates of telomerase activity of malignant GIST, potential malignant GIST and benign GIST were 85% (17/20), 22.8% (2/9) and 0 (0/9), respectively. The apoptosis indices of malignant GIST, potential malignant GIST, and benign GIST were 11.7 ± 5.4, 30.2 ± 5.6 and 45.2 ± 7.2, respectively. The intensity of telomerase activity and apoptosis were related to the biological characteristics of GISTs (85% vs 22.8%, 0, 0; P < 0.01 or 11.7 ± 5.4 vs 30.2 ± 5.6, 45.2 ± 7.2, 72.1 ± 9.3; P < 0.05). The intensity of telomerase activity was negatively correlated with cellular apoptosis (22.9 ± 8.4 vs 9.5 ± 5.7, P < 0.01). The intensity of telomerase activity was positively correlated with p53, bcl-2 expression (40.0% vs 78.9%, 40.0% vs 84.2%; P < 0.05).
CONCLUSION: The detection of telomerase activity, apoptosis and its control genes in GIST will be helpful for the discrimination of the malignant and benign GIST and evaluation of the prognosis.
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Affiliation(s)
- Qiang Wang
- Department of Gastrointestinal Surgery, Shenjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
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Lagarde SM, ten Kate FJW, Richel DJ, Offerhaus GJA, van Lanschot JJB. Molecular prognostic factors in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol 2006; 14:977-91. [PMID: 17122988 DOI: 10.1245/s10434-006-9262-y] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2006] [Revised: 09/25/2006] [Accepted: 09/25/2006] [Indexed: 12/20/2022]
Abstract
OBJECTIVE This review describes genetic and molecular changes related to adenocarcinoma of the esophagus and gastroesophageal junction (GEJ) with emphasis on prognostic value and possibilities for targeted therapy in clinical setting. Adenocarcinoma of the esophagus or GEJ is an aggressive disease with early lymphatic and hematogenous dissemination. Molecular pathology has revealed many molecular mechanisms of disease progression, which are related to prognosis. Some of these factors can be seen as prognostic factors per se. Better knowledge of molecular bases may lead to new paradigms, improved prognostication, early diagnosis and individually tailored therapeutic options. METHODS A review of recent English literature (1990-October 2005) concerning esophageal adenocarcinoma was performed. This review focuses on genetic and molecular changes as prognosticators of adenocarcinoma of the esophagus and GEJ. RESULTS A bewildering number of biomarkers have been described. Many genes and molecules have prognostic impact (cyclin D1, EGFR, Her-2/Neu, APC, TGF-beta, Endoglin, CTGF, P53, Bcl-2, NF-kappaB, Cox-2, E-cadherin, beta-catenin, uPA, MMP-1,3,7,9, TIMP, T( h )1/T( h )2 balance, CRP, PTHrP). CONCLUSIONS Adenocarcinomas of the esophagus and GEJ show multiple genetic alterations, which indicate that progression of cancer is a multistep complex process with many different alterations. Presumably, it is not one molecular factor that can predict the biological behavior of this cancer. The combination of diverse genetic alterations may better predict prognosis. In future, gene expression analysis with microarrays may reveal important prognostic information and the discovery of new genes and molecules associated with tumor progression and dissemination will enhance prognostication and offers adjuvant therapeutic options.
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Affiliation(s)
- S M Lagarde
- Department of Surgery, Academic Medical Center at the University of Amsterdam, 1105, AZ, Amsterdam, The Netherlands.
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Dreilich M, Lindkvist A, Dhar S, Paulsson-Karlsson Y, Brattström D, Nygren P, Rickardson L, Wagenius G, Bergqvist M. Telomerase activity is not a key determinant of sensitivity to standard cytotoxic drugs in human esophageal carcinoma cell lines. Anticancer Drugs 2006; 17:503-9. [PMID: 16702806 DOI: 10.1097/00001813-200606000-00003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The aim of the present study was to investigate if basal telomerase activity levels may predict sensitivity to cytotoxic drugs in a panel of human esophageal carcinoma cell lines. The TRAPeze telomerase detection assay was used to investigate telomerase activity in the cell lines. Cytotoxic drug sensitivity for 20 standard cytotoxic agents was assessed using the fluorometric microculture cytotoxicity assay (FMCA). Telomerase activity was detected in all cell lines with a broad range of activity levels. Drug sensitivity also varied considerably between the cell lines. Except for a P value towards a correlation between mitoxantrone and telomerase activity (P=0.054), no statistically significant correlation was found between telomerase activity levels and sensitivity to investigated drugs, including key drugs such as cisplatin (P=0.9), 5-fluorouracil (P=0.8) and doxorubicin (P=0.54). We therefore conclude that basal telomerase activity level is not a key determinant of sensitivity to standard cytotoxic drugs in esophageal carcinoma cell lines.
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Affiliation(s)
- Martin Dreilich
- Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University Hospital, Uppsala, Sweden
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Bergqvist M, Brattström D, Brodin D, Lindkvist A, Dahlman-Wright K, Dreilich M, Wagenius G, Paulsson-Karlsson Y. Genes associated with telomerase activity levels in esophageal carcinoma cell lines. Dis Esophagus 2006; 19:20-3. [PMID: 16364039 DOI: 10.1111/j.1442-2050.2006.00532.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Telomerase activity levels have been shown to correlate with tumor progression in several malignancies. However, the genetic regulation of telomerase activity levels is not fully understood. The aim of the present study has been to identify a gene expression profile, predicting correlation with the telomerase-activity test. Ten human esophageal carcinoma cell lines were investigated using the telomerase activity assay (TRAPeze) Telomerase Detection Kit), followed by further characterization using the GeneChip Human Genome U133A 2.0 Array (Affymetrics Inc., USA), including 14 500 human genes. Telomerase activity levels were detected in all cell lines with a broad range of activity levels. Using a high correlation coefficient, r > 0.90, the following genes were found to be positively correlated with telomerase activity levels: N-myristoyltransferase 2; ribosomal protein L3; retinoblastoma-like 2 (pRb2/p130); and cyclin G2. Only one gene was negatively correlated with telomerase activity levels, zinc finger protein 207. In conclusion, the present microarray data provide primary validation data indicating possible candidates for prognostic and prediction factors in esophageal cancer in relation to telomerase activity.
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Affiliation(s)
- M Bergqvist
- Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
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Barclay JY, Morris AG, Nwokolo CU. HTERT mRNA partially regulates telomerase activity in gastric adenocarcinoma and adjacent normal gastric mucosa. Dig Dis Sci 2005; 50:1299-303. [PMID: 16047476 DOI: 10.1007/s10620-005-2776-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
The extent to which human telomerase reverse transcriptase (hTERT) mRNA and its splice variants control telomerase activity in human cancers is controversial. Telomerase and hTERT mRNA were assessed quantitatively in paired samples of gastric adenocarcinoma and adjacent normal tissue. Splice variants within the hTERT reverse transcriptase domain (alpha, beta, alphabeta) were detected by RT-PCR. In gastric adenocarcinoma, compared to normal tissue, median telomerase activity increased significantly (from 0 total product generated [tpg; 95% confidence interval CI, 0-2.3] to 16.1 tpg [95% CI, 3.7-97]; P = 0.008) and median hTERT mRNA levels also increased (from 2.21 [95% CI, 1.40-4.62] to 7.08 [95% CI, 3.26-10.8]; P = 0.0054). hTERT mRNA and telomerase activity correlated in normal gastric mucosa (r = 0.819, P = 0.0002). Alpha, beta, and alphabeta deletions were similar in both groups. We conclude that hTERT mRNA partially regulates telomerase activity in normal gastric mucosa and gastric adenocarcinoma. In contrast, hTERT mRNA splicing is not involved in the regulation of enzyme activity.
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Affiliation(s)
- J Y Barclay
- University Hospitals Coventry and Warwickshire and Department of Biological Sciences, University of Warwick, Coventry, UK
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Gulmann C, Lantuejoul S, Grace A, Leader M, Patchett S, Kay E. Telomerase activity in proximal and distal gastric neoplastic and preneoplastic lesions using immunohistochemical detection of hTERT. Dig Liver Dis 2005; 37:439-45. [PMID: 15893283 DOI: 10.1016/j.dld.2005.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2004] [Accepted: 01/18/2005] [Indexed: 12/11/2022]
Abstract
BACKGROUND The incidence of distal (corpus and antrum) gastric adenocarcinoma is decreasing with a simultaneous increase in incidence of proximal (cardia) adenocarcinoma. Epidemiological studies suggest that they may represent different diseases but corroborative molecular data are scarce. Intestinal metaplasia may have a lower malignant potential in the proximal stomach but regardless of the locations, its specificity as a predictor of carcinoma is low. AIMS The aim of this study was to establish whether human telomerase reverse transcriptase expression differs at various points in proximal versus distal gastric carcinogenesis and to test the utility of human telomerase reverse transcriptase expression as a marker of cancer risk in intestinal metaplasia. MATERIAL AND METHODS Wax-embedded tissue from proximal and distal stomach including normal mucosa (n=86), intestinal metaplasia (n=83) and carcinoma (n=101) were used and slides were immunostained for human telomerase reverse transcriptase and pRb and scored semi-quantitatively. RESULTS The results showed that in both proximal and distal stomach, human telomerase reverse transcriptase expression rates increased from normal mucosa to cancer. High rates of human telomerase reverse transcriptase expression were seen in the proliferative zones of glands in intestinal metaplasia. In both the locations, loss of pRb expression correlated with higher human telomerase reverse transcriptase expression. CONCLUSIONS In conclusion, telomerase activity appears to be an early event in both proximal and distal gastric carcinogenesis and human telomerase reverse transcriptase is expressed in intestinal metaplasia. Telomerase re-expression may be facilitated by pRb inactivation.
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Affiliation(s)
- C Gulmann
- Department of Pathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland.
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14
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Ye J, Wu YL, Zhang S, Chen Z, Guo LX, Zhou RY, Xie H. Inhibitory effect of human telomerase antisense oligodeoxyribonucleotides on the growth of gastric cancer cell lines in variant tumor pathological subtype. World J Gastroenterol 2005; 11:2230-7. [PMID: 15818731 PMCID: PMC4305804 DOI: 10.3748/wjg.v11.i15.2230] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory effect of specialized human telomerase antisense oligodeoxyribonucleotides on the growth of well (MKN-28), moderately (SGC-7901) and poorly (MKN-45) differentiated gastric cancer cell lines under specific conditions and its inhibition mechanism, and to observe the correlation between the growth inhibition ratio and the tumor pathologic subtype of gastric cancer cells.
METHODS: Telomerase activity in three gastric cancer cell lines of variant tumor pathologic subtype was determined by modified TRAP assay before and after the specialized human telomerase antisense oligodeoxyribonucleotides were dealt with under specific conditions. Effect of antisense oligomer under specific conditions of the growth and viability of gastric cancer cell lines was explored by using trypan blue dye exclusion assay, and cell apoptosis was detected by cell morphology observation, flow cytometry and TUNEL assay.
RESULTS: Telomerase activity was detected in well, moderately and poorly differentiated gastric cancer cell lines (the quantification expression of telomerase activity was 43.7TPG, 56.5TPG, 76.7TPG, respectively).Telomerase activity was controlled to 30.2TPG, 36.3TPG and 35.2TPG for MKN-28, SGC-7901 and MKN-45 cell lines respectively after treatment with human telomerase antisense oligomers at the concentration of 5 μmol/L, and was entirely inhibited at 10 μmol/L, against the template region of telomerase RNA component, whereas no inhibition effect was detected in missense oligomers (P<0.05). After treatment with antisense oligomers at different concentrations under specific conditions for 96 h, significant growth inhibition effects were found in MKN-45 and SGC-7901 gastric cancer cell lines (the inhibition ratio was 40.89% and 71.28%), but not in MKN-28 cell lines (15.86%). The ratio of inactive SGC-7901 cells increased according to the prolongation of treatment from 48 to 96 h. Missense oligomers could not lead to the same effect (P<0.05). Apoptosis of SGC-7901 and MKN-45 cells was detected not only by morphology and TUNEL assay but also by flow cytometry. The apoptotic rate reached 33.56% for SGC-7901 cells and 44.75% for MKN-45 cells.
CONCLUSION: The viability and proliferation of gastric cancer cells can be inhibited by antisense telomerase oligomers. The growth inhibition of gastric cancer cells is correlated with concentration, time and sequence specialty of antisense oligomers. The inhibition mechanism of antisense human telomerase oligomers depends not only on the sequence specialty but also on the biological characteristics of gastric cancer cell lines.
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Affiliation(s)
- Jing Ye
- Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China
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Yoo J, Park SY, Kang SJ, Kim BK, Shim SI, Kang CS. Expression of telomerase activity, human telomerase RNA, and telomerase reverse transcriptase in gastric adenocarcinomas. Mod Pathol 2003; 16:700-7. [PMID: 12861067 DOI: 10.1097/01.mp.0000077517.44687.b6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosome ends to compensate for sequence loss during DNA replication. It has been detected in 85-90% of all primary human cancers, implicating that the telomerase seems to be reactivated in tumors and that such activity may play a role in the tumorigenic process. The purpose of this study was to evaluate telomerase activity, human telomerase RNA (hTR), and telomerase reverse transcriptase (TERT) in stomach cancer and to determine their potential relationships to clinicopathologic parameters. Frozen and corresponding methacarn-fixed paraffin-embedded tissue samples were obtained from 51 patients with gastric adenocarcinoma and analyzed for telomerase activity by using a TRAPeze ELISA kit. Tissue sections of all the samples were further investigated for hTR and TERT by in situ hybridization and a sensitive immunohistochemical technique, respectively. Telomerase activity was detected in 37 (73%) tumors. Telomerase positivity from methacarn-fixed paraffin blocks was found to be 35% of that from frozen tissues. hTR was overexpressed in 46 (90%) samples: 33/37 (89%) with and 13/14 (93%) without telomerase activation. Expression of TERT was demonstrated in 40 (78%) cases: 30/37 (81%) with and 10/14 (71%) without telomerase. Telomerase activity correlated well with depth of invasion (P =.037) and tumor differentiation (P =.022), whereas hTR significantly correlated with nodal metastasis (P=.047) and tumor size (P=.023). These data suggest that reactivated telomerase may play a significant role in the tumorigenesis of gastric cancer and may reflect, along with enhanced hTR, the malignant potential of the tumor. It is noteworthy that methacarn-fixed tissue cannot as yet substitute for the frozen section in the TRAP assay.
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Affiliation(s)
- Jinyoung Yoo
- Department of Pathology, St. Vincent's Hospital, Catholic University, Suwon, South Korea
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Abstract
Telomerase, a critical enzyme responsible for continuous cell growth, is repressed in most somatic cells except proliferating progenitor cells and activated lymphocytes, and activated in approximately 85% of human cancer tissues. Telomerase activity is a useful cancer-cell detecting marker in some types of cancers in which almost all cases show telomerase activation. In other types in which telomerase becomes upregulated according to tumor progression, it is a useful prognostic indicator. Detection of human telomerase reverse transcriptase (hTERT) mRNA or protein in various clinical samples is also applicable. However, careful attention should be paid to the false negative results due to the instability of this enzyme or hTERT mRNA and the existence of polymerase chain reaction inhibitors as well as the false-positive results due to the contamination by normal cells with telomerase activity. If these pitfalls are avoided, in situ detection of hTERT mRNA or protein will facilitate the reliability of telomerase as a tumor marker.
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18
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Abstract
There is a constant balance in cancer cells between division and death. The malignant phenotype is associated with a continuing cell cycle or 'immortalization'. Telomeres, structures that cap the chromosomes, are related to cell longevity and are regulated by a ribonucleoprotein called telomerase. This review describes the possible roles of telomeres and telomerase in the malignant process.
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Affiliation(s)
- J Crocker
- Department of Cellular Pathology, Birmingham Heartlands Hospital, Birmingham, UK.
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