High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus

Bonatz, G.; Frahm, Sven Olaf; Klapper, Wolfram; Helfenstein, Andreas; Heidorn, Klaus; Jonat, W.; Krupp, Guido; Parwaresch, Reza; Rudolph, Pierre

doi:10.1053/hupa.2001.25002

Cited by 30 publications

(27 citation statements)

References 41 publications

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“…In addition, telomerase expression has been linked to chromosome healing and increased cell survival (5,6). Cell cycle analysis has further associated high telomerase activity with an increased rate of cells entering the S phase and a high degree of malignancy (7). These findings suggest that telomerase may affect both cancerrelated genes and biological pathways in addition to maintaining telomere length and might consequently contribute to the initiation of tumor development.…”

Section: Introductionmentioning

confidence: 92%

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Xing

Zhu

Zhao³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Expression of telomerase is one of the hallmarks of tumor cells and has been used as a diagnostic biomarker and a therapeutic target in cancer. Novel findings have shown that telomerase activation in normal human epithelial cells may affect expression of several cancer-related genes, such as growth-related genes and c-myc gene, suggesting a possible role of telomerase in tumor initiation. Therefore, we hypothesized that individuals who are sensitive to mutagen challenge in terms of induced telomerase activity might have increased cancer risk. We tested this hypothesis in a bladder cancer case-control study (51 cases and 51 matched controls) by measuring baseline and ;-radiation -induced telomerase activities in peripheral blood lymphocytes. We found a significantly higher ;-radiation -induced telomerase activity in bladder cancer cases compared with the controls (1.34 versus 1.23; P = 0.044). A similar finding was also observed using the normalized telomerase activity (ratio of ;-radiation induced versus baseline; 1.49 versus 1.19; P < 0.001). In further categorizing the telomerase activity using 75% of the normalized value in the controls as a cutoff point, we found a significantly increased risk for bladder cancer associated with higher induced telomerase activity (adjusted odds ratio, 3.62; 95% confidence interval, 1.38-9.51). In quartile analysis, a dose-response association was noted between the induced telomerase activity and increased bladder cancer risk (P trend = 0.005). Our findings provide the first evidence linking the mutagen-induced telomerase activity in peripheral blood lymphocytes to the risk of bladder cancer, which warrants further investigation in large-sized studies and other cancer types. (Cancer Epidemiol Biomarkers Prev 2007;16(3):606 -9)

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Section: Introductionmentioning

confidence: 92%

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Xing

Zhu

Zhao³

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Telomerase activity and hTERT mRNA expression are closely associated in human cancers (4). It is not yet established whether telomerase activity merely mirrors the fraction of proliferating cells, or whether aggressively growing cells independently up-regulate their telomerase levels during malignant transformation (7).…”

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confidence: 99%

Immunohistochemical Detection of Human Telomerase Reverse Transcriptase (hTERT), Topoisomerase II?? Expression, and Apoptosis in Endometrial Adenocarcinoma and Atypical Hyperplasia

Brustmann

2005

International Journal of Gynecological Pathology

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This study evaluated the immunohistochemical expression of human telomerase reverse transcriptase (hTERT) in endometrial carcinoma and atypical endometrial hyperplasia, and related it to the expression of topoisomerase (TP)IIalpha (a proliferation associated enzyme); apoptosis as determined by the frequency of apoptotic bodies (ABI); mitotic counts; and other clinicopathologic variables. Immunoreactivity for hTERT and TPIIalpha as well as ABI were assessed in 57 endometrial samples (12 atypical hyperplasias, 33 endometrioid carcinomas, 12 serous/clear cell carcinomas). hTERT immunoreactivity, TPIIalpha labeling indices (LI), ABI, and ratios of the indices (ABI/TPIIalpha LI) increased from atypical hyperplasias to endometrioid carcinomas to serous/clear cell carcinomas (p < 0.0001 for each variable). hTERT expression increased with ABI (p < 0.0001), TPIIalpha LI (p = 0.0019), ABI/TPIIalpha ratios (p < 0.0001), and grade (p = 0.0005), but not with FIGO stage (p = 0.2775). TPIIalpha LI, ABI, and ratios were related to high grade (p = 0.0001 for each variable), but not with FIGO stage (p = 0.7362, p = 0.7554, and p = 0.7405, respectively). TPIIalpha LI and ABI were significantly correlated in atypical hyperplasias (p = 0.0004), endometrioid carcinomas (p < 0.0001), and serous/clear cell carcinomas (p = 0.024). Immunostaining levels for hTERT were similar in atypical hyperplasias and grade 1 endometrioid carcinomas (p = 0.1956). These results suggest that hTERT expression is closely related to proliferation, apoptosis, and high grade in endometrial carcinomas, reflecting cell cycle deregulation in endometrial carcinogenesis.

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“…With each cell division, telomeres are progressively shortened because of the inability of the DNA polymerase complex to replicate the 59 end of the lagging strand. 3 This shortening of telomeres may function as a mitotic clock, by which normal cells count their divisions and eventually signal their senescence. 2,3 Telomerase is a ribonuclein complex that extends and maintains telomeres.…”

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confidence: 99%

“…3 This shortening of telomeres may function as a mitotic clock, by which normal cells count their divisions and eventually signal their senescence. 2,3 Telomerase is a ribonuclein complex that extends and maintains telomeres. By activation of this enzyme cells are able to overcome replicative senescence and to divide indefinitely.…”

mentioning

confidence: 99%

“…2 This view is supported by observations that telomerase is frequently activated in many kinds of cancers or cancer cell lines but not in most normal tissues. 2,3 There are 2 major subunits of the telomerase enzyme complex that contribute to in vitro enzymatic activity. Human telomerase RNA component is an intrinsic RNA component that contains a template region and binds to TTAGGG repeats in telomeres.…”

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confidence: 99%

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Expression of Human Telomerase Reverse Transcriptase in Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma: An Immunohistochemical Study With Survivin and p53

Wellenhofer¹,

Brustmann²

2012

Archives of Pathology &Amp; Laboratory Medicine

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N Context.-Human telomerase reverse transcriptase (hTERT), an enzyme that enables cells to overcome replicative senescence and to divide indefinitely, is overexpressed in many cancers and their precursor lesions.Objective.-To test whether hTERT expression is related to neoplastic progression and resistance to apoptosis in vulvar epithelia.Design.-Immunoexpression of hTERT was evaluated in 101 formalin-fixed, paraffin-embedded archival vulvar epithelia consisting of normal squamous vulvar epithelia (n = 25), lichen sclerosus (n = 10), high-grade classic vulvar intraepithelial neoplasia (n = 16), differentiated vulvar intraepithelial neoplasia (n = 18), and vulvar invasive keratinizing squamous cell carcinoma (n = 32) and related to survivin and p53 expression. Immunostaining for all factors was scored for moderate and strong intensities with regard to quantity to determine upregulation and overexpression (score 0, 0% immunoreactive cells; score 1+, ,5% immunoreactive cells; score 2+, 5% to 50% immunoreactive cells; score 3+, .50% immunoreactive cells). Score 3+ was considered as overexpression.Results.-Nuclear hTERT immunoexpression was closely related to survivin reactivity, increased from normal vulvar squamous epithelia to lichen sclerosus and to high-grade classic vulvar intraepithelial neoplasia, differentiated vulvar intraepithelial neoplasia, and invasive keratinizing squamous cell carcinoma (P , .001), and followed the morphologic distribution of atypical squamous epithelial cells. Overexpression of hTERT was comparable to that seen for p53 in invasive keratinizing squamous cell carcinoma (P = .62); significant differences were calculated for differentiated vulvar intraepithelial neoplasia (P = .003) and highgrade classic vulvar intraepithelial neoplasia (P = .001).Conclusion.-Human telomerase reverse transcriptase is upregulated in vulvar intraepithelial neoplasia and invasive keratinizing squamous cell carcinoma compared with nonneoplastic squamous epithelia of the vulva as an apparently early and preinvasive event in the neoplastic transformation, with development of cellular longevity and resistance to apoptosis by survivin activation as associated features, independent of the etiology of vulvar intraepithelial neoplasia.(Arch Pathol Lab Med. 2012;136:1359-1365; doi: 10.5858/arpa.2011-0440-OA) I nvasive squamous cell carcinoma (ISCC) is the most common type of all invasive vulvar cancers. Vulvar intraepithelial neoplasias (VINs) are precancerous changes, defined as proliferative intraepithelial squamous lesions that display abnormal growth, exhibiting lack of cellular maturation and crowding of cells. According to the grade of dysplasia, they are designated as VIN grade 1, 2, or 3. The vast majority of VIN lesions are considered grade 2 or 3, with a distinction between these 2 grades being highly subjective. Basaloid and warty (condylomatous) or classic subtypes of VIN are associated with relatively younger women, and evidence of human papillomavirus (HPV) nucleic acids. A third, ''differentiated'' su...

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High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus

Cited by 30 publications

References 41 publications

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Differential Induction in Telomerase Activity among Bladder Cancer Patients and Controls on γ-Radiation

Immunohistochemical Detection of Human Telomerase Reverse Transcriptase (hTERT), Topoisomerase II?? Expression, and Apoptosis in Endometrial Adenocarcinoma and Atypical Hyperplasia

Expression of Human Telomerase Reverse Transcriptase in Vulvar Intraepithelial Neoplasia and Squamous Cell Carcinoma: An Immunohistochemical Study With Survivin and p53

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