Telomerase activity in bladder carcinoma and its implication for noninvasive diagnosis by detection of exfoliated cancer cells in urine

Yoshida, Kazuhiro; Sugino, Takashi; Tahara, Hidetoshi; Woodman, Anthony C.; Bolodeoku, John; Nargund, Vinod; Fellows, G. J.; Goodison, Steven; Tahara, Eiichi; Tarin, David

doi:10.1002/(sici)1097-0142(19970115)79:2<362::aid-cncr20>3.0.co;2-y

Cited by 185 publications

(92 citation statements)

References 24 publications

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“…It was shown that, regardless of tumour stage or degree of di erentiation, telomerase activity could be identi®ed in nearly all tissue samples derived from bladder carcinomas (Table 1) but not in normal urothelium. Thus, the fundamental prerequisites for a diagnostic method with high sensitivity and speci®city are ful®lled (Gelmini et al, 2000;Ito et al, 1998a;Kamata et al, 1996;Kinoshita et al, 1997;Kyo et al, 1997;Lancelin et al, 2000;Lee et al, 1998;Lin et al, 1996;Linn et al, 1997;May®eld et al, 1998;MuÈ ller et al, 1996;Rahat et al, 1999;Yokota et al, 1998;Yokota et al, 1998;Yokota et al, , 1996), low levels of telomerase activity were identi®ed in dysplastic urothelium by Lin et al (1996) in one of two cases and by Yoshida et al (1997) in two of two cases. In a very small number of cases, telomerase activity was detected in histologically normal urothelial tissue immediately adjacent to con®rmed tumours.…”

Section: Tissue Samplesmentioning

confidence: 99%

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Telomerase: Its clinical relevance in the diagnosis of bladder cancer

Müller

2002

Oncogene

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More than 50 years ago, Papanicolaou recognized the importance of a non-invasive technique for the diagnosis and follow-up of patients with carcinoma of the urinary bladder. Cystoscopy, however, has remained the`gold standard' since no currently available non-invasive method can compete with cystoscopy's sensitivity and speci®city. The detection of the ribonucleoprotein telomerase or the telomerase subunits human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) in urine samples o er new diagnostic perspectives. The present article presents a review of publications in the literature and evaluates their clinical relevance. The experimental studies reported to date are very promising and show that telomerase exactly ful®ls the requirements for a good diagnostic marker for carcinoma of the urinary bladder. The diagnostic application remains in an experimental stage and telomerase is still several steps away for routine use as a clinical parameter. The remaining steps leading to its routine clinical application will be discussed.

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Section: Tissue Samplesmentioning

confidence: 99%

“…Sensitivities for urine samples have ranged between 0% and 100% ( Rahat et al, 1999;Ramakumar et al, 1999;Yokota et al, 1998;Yoshida et al, 1997). The reasons for these widely divergent ®ndings remain unclear, particularly because methodical di erences, such as in the treatment of the samples, are not apparent.…”

Section: Urine Samplesmentioning

confidence: 99%

Telomerase: Its clinical relevance in the diagnosis of bladder cancer

Müller

2002

Oncogene

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“…Expression of rTERT was evaluated by comparison of the results with those of normal controls at each experimental stage. Telomere length assay To analyze telomere length, we employed southern hybridization for terminal restriction fragments (TRFs) using a (TTAGGG) 4 probe. Genomic DNA was extracted from a mixture of exfoliated urothelial cells from ten rats.…”

Section: Methodsmentioning

confidence: 99%

“…It has been reported that 80 to 90% of bladder tumors express telomerase activity, 2) and that the detection of telomerase activity in bladder tumor tissues and/or in exfoliated tumor cells in urine is useful as a new diagnostic tool. 3,4) To examine the critical point at which telomerase activation occurs in the course of bladder carcinogenesis, we measured telomerase activity in bladder epithelium during N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) carcinogenesis in the rat. BBN bladder carcinogenesis is thought to be a model for superficial bladder tumor.…”

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confidence: 99%

Telomerase Is Upregulated in Irreversible Preneoplastic Lesions during Bladder Carcinogenesis in Rats

Shimazui¹,

Ami²,

Miyanaga³

et al. 2002

Japanese Journal of Cancer Research

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Multiple occurrence or recurrence after transurethral resection is an important characteristic of superficial bladder tumors. To study bladder carcinogenesis, we focused on detection of telomerase activation, which was investigated in several human cancers, including bladder tumors. We experimentally examined the telomerase activity during bladder carcinogenesis, especially in precancerous lesions, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Male Wistar rats were given 0.05% BBN in water from the age of 8 weeks to 24 weeks. Subgroups were euthanized at 4, 8, 10, 12, 18, and 24 weeks after BBN administration. Using the stretch PCR method, telomerase activity was semiquantified in exfoliated bladder epithelial cells. In addition, telomere length in each subgroup was measured by southern hybridization for the terminal restriction fragment using a (TTAGGG) 4 probe. Statistical analyses were performed using analysis of variance and Fisher's PLSD test. Epithelial cells of normal bladder in the control groups and those of diffuse hyperplasia, which was a reversible change at 4 weeks, expressed no telomerase activity. In contrast, telomerase activity significantly increased in the stage after nodular hyperplasia, an irreversible change at 8 weeks, then elevated with carcinogenesis. However, telomere length was still preserved by the 12th week, and was shortened at 18 and 24 weeks. These results suggest that telomerase activation is probably induced independent of telomere shortening during bladder carcinogenesis in the rat, and might be a biological tumor marker of irreversible preneoplastic lesions, which evolve into bladder tumors in the rat. Key words: Bladder carcinogenesis -Telomerase -Telomere -BBN -HyperplasiaTelomerase is a ribonucleoprotein complex that synthesizes telomeric DNA and contributes to the maintenance of telomeres, which are composed of TTAGGG repeats located at the end of the chromosome and play a critical role in chromosome structure and function.1) A certain length of telomere is important for cell division; normal somatic cells express very low or undetectable levels of telomerase activity, and progressively lose their telomeric sequence via cell division. Therefore, the activation of this enzyme has been proposed to be a critical event in the immortalization of the cell, and is characteristic of most cancer cells. It has been reported that 80 to 90% of bladder tumors express telomerase activity, 2) and that the detection of telomerase activity in bladder tumor tissues and/or in exfoliated tumor cells in urine is useful as a new diagnostic tool. 3,4) To examine the critical point at which telomerase activation occurs in the course of bladder carcinogenesis, we measured telomerase activity in bladder epithelium during N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) carcinogenesis in the rat. BBN bladder carcinogenesis is thought to be a model for superficial bladder tumor. It has been well described that during bladder cancer development, diffuse hyperplasia at 4 weeks after BBN a...

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“…To date, there are no established tumour markers available, although several have been investigated in preliminary studies with promising results in terms of diagnostic or prognostic use. These include bladder-tumour associated analyte (BTA; Sarosdy et al, 1995;D'Hallewin and Baert, 1996;Leyh et al, 1997), nuclear matrix protein 22 (NMP22; Soloway et al, 1996), telomerase activity (Kinoshita et al, 1997;Yoshida et al, 1997), Ki-67 antigen and p53 protein expression (Tsuji et al, 1997), microsatellite analysis (Mao et al, 1996;Steiner et al, 1997) and matrix metalloproteinases, their inhibitors and activators (Gohji et al, 1998;Kanayama et al, 1998).…”

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confidence: 99%

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer

et al. 1999

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Summary Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

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Telomerase activity in bladder carcinoma and its implication for noninvasive diagnosis by detection of exfoliated cancer cells in urine

Abstract: These results suggest that telomerase could be a good diagnostic marker for the early noninvasive identification of patients with bladder carcinoma by facilitating the detection of exfoliated immortal cancer cells in their urine.

Cited by 185 publications

References 24 publications

Telomerase: Its clinical relevance in the diagnosis of bladder cancer

Telomerase: Its clinical relevance in the diagnosis of bladder cancer

Telomerase Is Upregulated in Irreversible Preneoplastic Lesions during Bladder Carcinogenesis in Rats

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer

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