Telomerase as a therapeutic target for malignant gliomas

Komata, Tadashi; Kanzawa, Takao; Kondo, Yasuko; Kondo, Seiji

doi:10.1038/sj.onc.1205072

Cited by 71 publications

(46 citation statements)

References 74 publications

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“…In addition, the level of hTERT transcripts appears to predict in GBMs decreased or increased survival. In the development and future application of anti-telomerase treatments of malignant gliomas (Komata et al, 2002), hTERT analysis of any given tumour will be essential.…”

Section: Discussionmentioning

confidence: 99%

Clinical implications of quantitative real-time RT–PCR analysis of hTERT gene expression in human gliomas

Tchirkov

Rolhion

Jl³

et al. 2003

Br J Cancer

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The presence of telomerase activity in a glioma may be a predictor of its malignant potential. Activation of telomerase is regulated at the transcriptional level of the human telomerase reverse transcriptase (hTERT). Here, we evaluated whether the amount of hTERT mRNA provides a molecular marker of glioma malignancy that would have clinical utility. We used a real-time RT -PCR to assess the number of hTERT transcripts in primary tumour samples derived from 70 glioma patients. Results were standardised by quantifying the number of ABL transcripts as internal control and expressed as hTERT/ABL ratio. The percentage of patients with detectable hTERT mRNA markedly increased with enhanced malignancy: low-grade gliomas expressed hTERT in one out of 14 cases (7.1%), anaplastic gliomas in four out of 13 cases (30.8%) and glioblastoma multiforme (GBM) tumours in 30 out of 43 cases (69.8%). The mean hTERT/ABL ratio was significantly higher in GBMs than in non-GBMs. Subdividing hTERT/ABL ratios as low (p25%) and high (425%), we found that the overall survival among hTERT-positive GBMs was significantly worse in high hTERT expressors than in low hTERT expressors (P ¼ 0.0082). We conclude that the amount of hTERT mRNA may represent a diagnostic and prognostic indicator for GBM patients.

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Section: Discussionmentioning

confidence: 99%

Clinical implications of quantitative real-time RT–PCR analysis of hTERT gene expression in human gliomas

Tchirkov

Rolhion

Jl³

et al. 2003

Br J Cancer

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“…Recently, telomerase has been recognized as a new wide-range tumor marker (Blackburn, 1991;Komata et al, 2002). It has been reported that telomerase activity is significantly higher in about 90% of cancers and correlates well with the degree of malignancy (Kim et al, 1994;Shay, 1997).…”

Section: Introductionmentioning

confidence: 99%

A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent

et al. 2004

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Telomerase is a therapeutic target for cancer. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionaly upregulated exclusively in about 90% of cancer cells. Previous studies have demonstrated that hTERT promoter can control the expression of exogenous genes to the telomerase-positive cancer cells, thus hTERT promoter is an excellent candidate for generating cancer-specific oncolytic adenovirus. In this study, we devised a novel oncolytic adenovirus (Ad.TERT) by replacing the normal E1A regulatory elements with hTERT promoter. Ad.TERT displays cancer-specific E1A expression, virus replication and cytolysis in in vitro experiments. In animal experiments, intratumoral administration of Ad.TERT demonstrates potent antitumoral efficacy at least in two xenograft models (Bcap37 and BEL7404). Ad.TERT was targeted by the telomerase activity in cancer cells and has potent antitumoral efficacy in vivo, and since telomerase activity is a wide-ranged tumor marker, Ad.TERT could be a powerful therapeutic agent for a variety of cancers.

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“…Whereas normal somatic cells have diminished telomerase activity, Ͼ90% of human cancers overexpress telomerase (5,6). The well established roles for telomerase in tumor initiation and cellular immortalization (7,8) have led to the identification of telomerase as a potentially important molecular target in cancer therapeutics (9)(10)(11). To date, multiple studies have examined the utility of targeting telomerase to inhibit tumor cell proliferation (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Genes and pathways downstream of telomerase in melanoma metastasis

Bagheri

Nosrati

Li³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

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Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.differentiation ͉ glycolysis T elomerase is a ribonucleoprotein complex composed of core protein (telomerase reverse transcriptase) and RNA (telomerase RNA or TER) moieties. The most extensively characterized function of telomerase is to maintain the telomeric repeats capping the ends of eukaryotic chromosomes and thereby preserve their integrity by preventing end-to-end fusions (1-4). Whereas normal somatic cells have diminished telomerase activity, Ͼ90% of human cancers overexpress telomerase (5, 6). The well established roles for telomerase in tumor initiation and cellular immortalization (7,8) have led to the identification of telomerase as a potentially important molecular target in cancer therapeutics (9-11). To date, multiple studies have examined the utility of targeting telomerase to inhibit tumor cell proliferation (12-16).Although the importance of telomerase for tumor cell proliferation is well documented, its impact on tumor invasion and metastasis has been studied less. In our recent study, we used a systemic injection model of an effective anti-telomerase ribozyme to reveal that inhibiting telomerase activity in tumorbearing mice significantly reduces metastatic progression (16). Here, we examine the direct role played by telomerase in the metastatic potential of murine melanoma and characterize cellular pathways altered by telomerase suppression in tumor cells. We show that stable, ribozyme-mediated suppression of TER levels in melanoma cells results in a more dendritic phenotype, accompanied by increased tyrosinase expression and pigment production. Furthermore, we show that TER suppression results in down-regulation of glycolytic pathway genes and significantly reduces glucose metabolism, providing a mechanistic basis for the reduced metastatic capacity and increased pigment production observed. ResultsTo directly examine the role of te...

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Telomerase as a therapeutic target for malignant gliomas

Cited by 71 publications

References 74 publications

Clinical implications of quantitative real-time RT–PCR analysis of hTERT gene expression in human gliomas

Clinical implications of quantitative real-time RT–PCR analysis of hTERT gene expression in human gliomas

A novel oncolytic adenovirus targeting to telomerase activity in tumor cells with potent

Genes and pathways downstream of telomerase in melanoma metastasis

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