Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

Tabori, Uri; Wong, K.F.; Ma, Jing; Shago, Mary; Alon, Noa; Rutka, James T.; Bouffet, Éric; Bartels, Ute; Malkin, David; Hawkins, Cynthia

doi:10.1038/sj.bjc.6604652

Cited by 47 publications

(36 citation statements)

References 24 publications

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“…The results showed that Ab 3 (NCL-L-hTERT antibody) was not absorbed any more with the nucleolin peptide than were the other anti-hTERT antibodies. In agreement with other researchers (27,70,71,(88)(89)(90)(91)(92)(93)(94)(95)(96)(97) and despite the objection raised by Wu et al (64) the Ab 3 proved suitable for hTERT detection. Mitsuishi et al (98) not only confirmed the consideration of Wu et al (64), but also found excellent correlation between nucleolin expression and telomerase activity levels in Bowens's disease and in normal sunexposed skin.…”

Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squsupporting

confidence: 76%

“…Mitsuishi et al (98) not only confirmed the consideration of Wu et al (64), but also found excellent correlation between nucleolin expression and telomerase activity levels in Bowens's disease and in normal sunexposed skin. In the immunohistochemical study of Ridley et al (99) hTERT expression in ependymomas with Ab 3 showed very strong correlation with the outcome in pediatric intracranial ependymomas (95). Furthermore, Khurts et al (100) revealed experimentally that nucleolin interacts with telomerase and changes its subcellular localization.…”

Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squmentioning

confidence: 99%

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Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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Abstract.In previous studies we demonstrated telomerase activity in frozen tissues from BCC and their tumor-free margins by the PCR ELISA. In this study we examined in the same frozen sections immunohistochemical presence of hTERT in the nucleus. After fixation in acetone and methanol followed by steaming we used for visualization the antigenantibody reactions by APAAP. This was the best method of preparation of the frozen sections in our preliminary hTERT-study with squamous cell carcinomas. This study was supplemented with antibodies against Ki-67, nucleolin, common leucocyte antigen CD45 and mutated p53. The immunoreactive scores were determined and included the comparison with telomerase activity. The investigation of hTERT expression was performed in the tissues of 41 patients with BCC and control tissues of 14 patients without tumor. Eleven commercial antibodies were used for a nuclear staining of hTERT expression. With the anti-hTERT antibodies we looked for both satisfactory distribution and intensity of immunohistochemical labeling in the carcinomas and in the squamous epithelia of the tumor centers, of the tumor-free margins and of the control tissues. The hTERT expression in the BCC was distributed heterogeneously. The score values established by the anti-hTERT antibodies used were variably or significantly increased. In the stroma they tended to be negative, so we disregarded stroma hTERT. Proof of hTERT did not differ uniformly from telomerase activity. We compared the high with the lower median hTERT values in the Kaplan-Meier curve. Patients with lower hTERT scores in the center or tumor margin as shown by some of the antibodies suffered relapse earlier. Finally, we compared the hTERT expression in BCC tissues with the hTERT scores in HNSCC tissues from our previous study. Only one anti-hTERT antibody (our Ab 7) yielded significantly higher scores in BCC than in HNSCC.

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Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squsupporting

confidence: 76%

Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squmentioning

confidence: 99%

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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“…Toomey et al (65) explored hTERT expression in patients with an operable lung carcinoma using an anti-hTERT antibody by Santa Cruz (code C20) and found no correlation in the Kaplan-Meier curve between high hTERT expression and patient outcome. Tabori et al (66), using our Ab 3 in ependymomas, were able to demonstrate a significantly shorter survival time in patients with higher hTERT expression (p=0.05). In patients with a mamma carcinoma, hTERT as demonstrated by Elkak et al (67) using the NCL-hTERT antibody (our Ab 3) did not correlate in the ¯2 test with lymph node status, grading or tumor size.…”

Section: Correlation Of Htert Score Values and Telomerase Activity Inmentioning

confidence: 99%

“…Xiao et al (106) conclude from their studies on culture cells and tissues fixated in formalin that chicken IgG antibodies can have definite advantages over the commonly used mammal IgG antibodies and exhibit less non-specific staining. Irrespective of the afore-mentioned objections, many authors continue to use the monoclonal NCL-L-hTERT for immunohistochemical proof of hTERT (63,66,(107)(108)(109)(110)(111)(112).…”

Section: Cells Which May Be Responsible For Telomerase Activity Outsimentioning

confidence: 99%

Immunohistochemical determination of the appropriate anti-hTERT antibodies for in situ detection of telomerase activity in frozen sections of head and neck squamous cell carcinomas and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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Abstract.In previous studies we demonstrated telomerase activity in frozen tissue from head and neck squamous cell carcinoma (HNSCC) and their tumor-free tumor margins. In the present study frozen sections from the same tissues were examined for in situ presence of hTERT. In preliminary investigations we established that the most suitable method of tissue preparation was fixation in acetone and methanol followed by steaming and visualization by APAAP. Most of the assays involved eleven anti-hTERT antibodies and were supplemented with the inclusion of antibodies Ki-67, antinucleolin and CD45. hTERT expression was investigated in the tissues of 61 patients with HNSCC and 37 patients without tumor. Semi-quantitative immunoreactive scores were correlated with telomerase activity. We examined the prognostic significance of hTERT expression with Kaplan-Meier curves and tested the immunological specificity of the antibodies by immunoabsorption with two hTERT peptides and a nucleolin peptide. Nuclear staining of satisfactory distribution and intensity was achieved in seven anti-hTERT antibodies both in the carcinomas and in the squamous epithelia of the tumor resection margins and in the control tissues. Proof of hTERT did not differ from telomerase activity. The telomerase activity demonstrated in tumor-free resection margins and in control tissues did, however, correlate with lymphocytic-monocytic infiltration (CD45 expression). This telomerase activity might be related to nuclear hTERT expression in the squamous epithelium, given that the hTERT score values in the connective tissue tended to be negative. The prognostic significance of hTERT expression demonstrated on paraffin sections from different tumor localizations was not confirmed for the frozen sections of patients with HNSCC. The hTERT specificity of the monoclonal NCL-L-hTERT, whose use as an antibody against hTERT has been questioned, was reexamined with immunohistochemical methods, but the intensity of its immunoabsorption with the nucleolin peptide did not exceed that observed in the other anti-hTERT antibodies.

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“…These tumors, specifically gliomas and neuroblastomas, share unique extremes of clinicobiological behavior: spontaneous growth arrest, on the one hand, and relentless progression even with maximal therapy, on the other (2,3). Previous work from our group and others has shown that the lack of telomere maintenance is responsible for growth arrest and predicts the risk of recurrence in pediatric low-grade gliomas (2), ependymomas (4,5), and stage IV-S neuroblastomas (6), suggesting that telomerase inhibition could reverse their malignant phenotype by altering their self-renewal capabilities.…”

Section: Introductionmentioning

confidence: 99%

Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

Castelo‐Branco

Zhang

Lipman

et al. 2011

Clinical Cancer Research

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Purpose: Cancer recurrence is one of the major setbacks in oncology. Maintaining telomeres is essential for sustaining the limitless replicative potential of such cancers. Because telomerase is thought to be active in all tumor cells and normal stem cells, telomerase inhibition may be nonspecific and have detrimental effects on tissue maintenance and development by affecting normal stem cell self-renewal.Methods: We examined telomerase activity, telomere maintenance, and stem cell maturation in tumor subpopulations from freshly resected gliomas, long-term, primary, neural tumor-initiating cells (TIC) and corresponding normal stem cell lines. We then tested the efficacy of the telomerase inhibitor Imetelstat on propagation and self-renewal capacity of TIC and normal stem cells in vitro and in vivo.Results: Telomerase was undetectable in the majority of tumor cells and specific to the TIC subpopulation that possessed critically short telomeres. In contrast, normal tissue stem cells had longer telomeres and undetectable telomerase activity and were insensitive to telomerase inhibition, which results in proliferation arrest, cell maturation, and DNA damage in neural TIC. Significant survival benefit and late tumor growth arrest of neuroblastoma TIC were observed in a xenograft model (P ¼ 0.02). Furthermore, neural TIC exhibited irreversible loss of self-renewal and stem cell capabilities even after cessation of treatment in vitro and in vivo.Conclusions: TIC exhaustion with telomerase inhibition and lack of telomerase dependency in normal stem cells add new dimensions to the telomere hypothesis and suggest that targeting TIC with telomerase inhibitors may represent a specific and safe therapeutic approach for tumors of neural origin.

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Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma

Cited by 47 publications

References 24 publications

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Immunohistochemical determination of the appropriate anti-hTERT antibodies for in situ detection of telomerase activity in frozen sections of head and neck squamous cell carcinomas and tumor margin tissues

Neural Tumor-Initiating Cells Have Distinct Telomere Maintenance and Can be Safely Targeted for Telomerase Inhibition

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