Telomerase activity as a novel marker of lung cancer

Telomerase activity is found in more than 80% of human malignant neoplasms, including lung cancer. Markers with high incidence in malignant samples and very low incidence in benign samples are useful in clinical diagnosis of cancer. Thus, telomerase activity in clinical materials may become a novel tumor marker of existing lung cancer cells. Moreover, since activation of telomerase is associated with cellular immortality and its activity level is quite different between lung cancer tissues, the activity level may become an indicator of some biological features in lung cancer.     

Telomerase assay for diagnosis of esophageal cancer

Esophageal squamous cell carcinoma is one of the aggressive diseases that has poor outcome. Therefore it is appeared that early diagnosis is very important for improving its outcome. Iodine staining method is useful for detecting the abnormal squamous epithelium and unstaining lesions by iodine contain the early esophageal cancers. Recently, telomerase activity that provides an immortal capacity for the cells has been measured in many tissues. We measured the telomerase activity in the samples of unstaining lesion by iodine using a polymerase chain reaction-based assay and described the relation between telomerase activity and histopathological findings.     

Tumor-associated hyaluronic acid: a new sensitive and specific urine marker for bladder cancer

Hyaluronic acid (HA), a glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments stimulate angiogenesis. We compared levels of HA in the urine of normal individuals and patients with bladder cancer or other genitourinary conditions, using a sensitive ELISA-like assay. Among the 144 specimens analyzed, the urinary HA levels of bladder cancer patients with G1 (255 +/- 41.7 ng/mg), G2 (291.8 +/- 68.3 ng/mg) and G3 (428.4 +/- 67 ng/mg) tumors are 4-9-fold elevated as compared to those of normal individuals (44.7 +/- 6.2 ng/mg) and patients with other genitourinary conditions (69.5 +/- 6.8 ng/mg; P < 0.001). Urinary HA measurement by the ELISA-like assay shows a sensitivity of 91.9% and specificity of 92.8% to detect bladder cancer. Thus, urinary HA measurement is a simple, noninvasive yet highly sensitive and specific method for bladder cancer detection. The increase in urinary HA concentration is a direct correlate of the elevated tumor-associated HA levels, because the HA levels are also elevated (3-5-fold) in bladder tumor tissues (P < 0.001). The profiles of urinary HA species of normal individuals and bladder cancer patients are different. Although only the intermediate-size HA species are found in the urine of normal and low-grade bladder tumor patients, the urine of high-grade bladder cancer patients contains both the high molecular mass and the small angiogenic HA fragments. These urinary HA fragments stimulate a mitogenic response (2.4-fold) in primary human microvessel endothelial cells, suggesting that the small HA fragments may regulate tumor angiogenesis by modulating endothelial cell functions.     

Telomerase: a promising marker of biological immortality of germ, stem, and cancer cells. A review

This review will describe the current state of knowledge of telomerase as it relates to human malignancies, focusing primarily on published measurements of this enzymes activity in benign and malignant neoplasms and their normal tissue counterparts. Key questions concerning the potential clinical utility of assaying for telomerase activity will be addressed and the implications of recent findings discussed.     

Telomerase in cancer: clinical applications

The biology of telomeres and telomerase has been the subject of intensive investigative effort since it became evident that they play a significant role in two important biological processes, the loss of cellular replicative capacity inherent to organismal ageing and the unrestricted cell proliferation characteristic of carcinogenesis. Telomere shortening in normal cells is a result of DNA replication events, and reduction beyond a critical length is a signal for cellular senescence. One of the cellular mechanisms used to overcome proliferative restriction is the activation of the enzyme telomerase, which replaces the loss of telomeric DNA that occurs at each cell division. Studies have demonstrated that tumours have shorter telomeres than normal tissue and that telomerase is activated in up to 90% of all human cancers while it is present only in a limited range of normal adult tissues. The role of telomerase in the extension of the cellular replicative lifespan has recently been shown by ectopic expression of the enzyme, being consistent with the oncogenesis model whereby the acquisition of an 'immortal' phenotype is a requirement for advanced tumour progression. In this article we review the present knowledge of telomeres and telomerase in cancer and discuss the potential use of this enzyme as a diagnostic and prognostic tumour marker and as a target for cancer therapy.     

Telomerase and cancer

Telomeres progressively shorten with age in somatic cells in culture and in vivo because DNA replication results the loss of sequence at the 5' ends of double-stranded DNA. Whereas normal somatic cells do not express the enzyme, telomerase, which adds repeated telomere sequences to chromosome ends, telomerase activity is detected in immortalized and tumor cells in vitro and in tumor tissues. This represents an important difference between normal cells and cancer cells, indicating that the telomerase activity and/or expression profiles of telomerase components are useful markers for cancer biology and detection.     

Cyfra 21-1, a new marker of lung cancer

The are few outstanding serous markers in the treatment of bronchial cancer. ACE lacks sensitivity and specificity and cannot be used as a diagnostic marker. It has been described as a marker of tumoral mass, although not in our study. Prognostic significance was observed, but only in a univariate analysis. Sensitivity of SCC TA4 varied between studies. In our population, the ROC curve for SCC TA4 showed poor discrimination potential. NSE was shown to be a useful marker in the treatment of patients with small cell cancers. Cytokeratins are expressed by all bronchial cancers. Cytokeratin 19 is a sub-unit detected in simple epithelia and their neoplastic counterparts. During tumoral cell lysis, certain fragments of this cytokeratin may be liberated. The immunoradiometric assay described here is able to detect fragments of cytokeratin 19 (called Cyfra 21-1) in serum. Our study established a correlation between Cyfra 21-1 levels and the cancer stage for NCPC, but not for CPC. In addition, Cyfra 21-1 concentration may be used as a tumoral mass marker. Patients with high Cyfra 21 levels must undergo special treatment to find remote tumors.     

Carbohydrate-deficient transferrin: a new biochemical marker for chronic excessive alcohol consumption

OBJECTIVE: To assess the usefulness of the biochemical marker 'carbohydrate deficient transferrin' (CDT) in relation to conventional markers for chronic excessive alcohol use. DESIGN: Prospective. SETTING: Addiction clinic Paschalis, Wanssum, the Netherlands. METHOD: Addicts for weaning (n = 125) were questioned at admission about their drinking habits in the last two weeks. Based on the criterion more or less than 60 g alcohol per day, the group was divided into excessive and nonexcessive alcohol users (men: 52 abusers, 51 non-abusers; women: 12 abusers, 10 non-abusers). Mean cell volume (MCV), gamma-glutamyl transpeptidase (gamma GT) and total transferrin were measured in blood collected 2 days after admission, as well as CDT by two methods (CDTect and % CDTriTIA). RESULTS: In men the CDTect test was the most sensitive: sensitivity 82% with specificity 88%. The sensitivity and specificity were 62% and 86% for gamma GT, 50% and 95% for % CDTriTIA, and 34% and 98% for MCV. The combination of a positive CDTect result and a positive gamma GT result gave a predictive value of use of alcohol > 60 g/day of 100%. The results of CDT and gamma GT were also used for a logistic regression model, giving a statistical prediction for excessive alcohol use. The subgroups of women were too small to detect statistical significant differences between tests. CONCLUSION: The CDTect test was more sensitive for the detection of chronic excessive alcohol use than the conventional markers. The combination of gamma GT and CDTect results increased the positive predictive value.     

Serum CA 242: the search for a valid marker of pancreatic cancer

As experience with peritoneal dialysis (PD) has improved and peritonitis rates have decreased, more patients are surviving for long periods on PD. Associated with this has been the recognition that there are unique complications of PD, specifically sclerosing syndromes and membrane failure that are most common in the long-term patient. Although anecdotal data would suggest that the long-term exposure to "bio-incompatable" fluids and or the occurrence of severe episodes of peritonitis are contributory in the pathogenesis of these diseases, cause and effect have not been proven. Normal peritoneal structure, changes that occur over time, and how the normal resident immune defense systems are altered with PD are reviewed. It is known that the continued loss of macrophages in the PD fluid results in an ever increasing percentage of immature cells in the peritoneum, which paradoxically are more reactive in terms of cytokine generation and less effective in host defense. The potential harmful effects of glucose and advanced glycosylation end products are also explored. The review concludes stating that further research is needed to better link the clinical syndromes with alterations in membrane structure/function.     

Telomerase activity in human bladder cancer

Telomerase can synthesize telomeric DNA repeats onto chromosome ends. Telomere length and telomerase activity have recently been implicated in the control of the proliferative capacity of normal and malignant cells. The expression of telomerase activity is concomitant with the attainment of immortality in tumor tissues and cells. Thus, enzyme activity may indicate a prevalent or even ubiquitous tumor producer. In this report, telomerase activity was analyzed in 40 human bladder cancers, 7 normal tissues, and 2 bladder epithelia with dysplasia using a PCR-based telomeric repeat amplification protocol assay. Telomerase activity was detected in almost all bladder tumors (97.5%); only one sample, which was in an early stage, did not express telomerase activity. None of the normal tissues displayed telomerase activity. One of the two bladder epithelia with dysplasia expressed low telomerase activity. The expression of telomerase activity has a clear association with the pathological grade and clinical stage. Most of the tumors with high telomerase activity were in an advanced grade and had deep invasion. Thus, telomerase activity might be suggested to represent an additional required event in the multigenetic process of tumorigenesis in human bladder cancer.     

High bone mass as a marker for breast cancer risk

Postmenopausal women in the highest quartile for metacarpal bone mass were found to have an increased risk of developing breast cancer, after adjusting for age and other variables known to influence breast cancer risk. Although the mechanisms responsible for this relationship have not been identified, postmenopausal bone mass may serve as an indicator of cumulative estrogen exposure.     

QRS prolongation measured by a new computerized method: a sensitive marker for detecting exercise-induced ischemia

This study compared thallium stress testing and exercise changes in QRS duration using a computerized 'optic scanner' in three groups. Group 1 consisted of 108 subjects with positive exercise ECG tests by ST-T segment criteria and with proven coronary artery disease. Group 2 included 19 subjects with nondiagnostic exercise ECG ST-T changes and with proven coronary artery disease. Group 3 was formed by 38 healthy controls. Group 1: Mean increase in exercise QRS width of 12.4 +/- 14 ms. Group 3: Mean decrease in exercise QRS width of 4.9 +/- 9.3 ms (p < 0.0001). Group 2: Mean QRS prolongation of 7.8 +/- 9.2 ms, which was significantly different from the controls (p < 0.0001) but not from group 1. When compared to thallium stress testing, exercise QRS prolongation had a sensitivity of 93%, specificity of 71%, relative risk of 5, and positive predictive value of 86%. QRS duration measurement can improve the diagnostic accuracy of the exercise ECG stress test.     

Mitosin (a new proliferation marker) correlates with clinical outcome in node-negative breast cancer

Tumor proliferation rate is an important prognostic factor in breast cancer, and S-phase fraction (SPF), as measured by flow cytometry, is the most clinically validated of several methods for measuring it. However, flow cytometry is not well suited to evaluating the formalin-fixed, paraffin-embedded tumors that are routinely available or to the increasing number of small breast cancers. These and other limitations have motivated research into alternative methods for measuring proliferation, including immunohistochemistry (IHC) against cell cycle-related antigens, which are better suited for the evaluation of small archival tissue samples. Mitosin is a recently described 350 kD nuclear phosphoprotein that is expressed in the late G1, S, G2, and M phases of the cell cycle but not in G0. Using a new monoclonal antibody (14C10), this pilot study evaluated mitosin expression by IHC in a series of 386 node-negative, formalin-fixed, archival breast cancers and correlated the results with several prognostic factors and clinical outcome (median follow-up, 78 months; range 3-214 months). The median and range of mitosin positive cells were 7% and 1-47%, respectively. There was a strong positive correlation between mitosin and SPF (r = 0.57; P = 0.0001), and there were significant negative correlations with estrogen receptor, progesterone receptor, and patient age. Mitosin was not related to overall survival in this pilot study. However, in a univariate cutpoint analysis of disease-free survival (DFS), patients with high levels of mitosin (>9% positive cells) had significantly worse DFS than did patients with lower levels (68% versus 84% at 5 years, respectively). In a multivariate analysis of DFS, large tumor size (>2 cm) and high mitosin were the only independently significant predictors of recurrence (relative risks = 2.47 and 1.72, respectively) in a model containing the additional factors estrogen receptor, progesterone receptor, patient age, and SPF. These preliminary results suggest that mitosin as assessed by IHC may be superior to SPF as a prognostic factor in node-negative breast cancer, but additional studies are necessary to validate these promising findings.     

Hepatocyte growth factor(HGF): a new biochemical marker for acute myocardial infarction

The purpose of this study was to investigate the use of hepatocyte growth factor as a biochemical marker for acute myocardial infarction. Several biochemical markers are used for noninvasive detection of acute myocardial infarction. However, hepatocyte growth factor has not been used previously for this purpose. We measured hepatocyte growth factor, creatine phosphokinase, and MB isoenzyme (CK-MB) levels in 6 patients with stable effort angina after diagnostic catheterization (controls) and in 12 patients with acute myocardial infarction (AMI). The measurements in the AMI patients were recorded twice a day for the first 3 days after onset of chest pain and once a day for the next 4 days. Furthermore, in each patient we evaluated the time to reach the maximum level and the time for the level to decline to less than half the maximum. Hepatocyte growth factor levels (ng/ml) were 0.3+/-0.1 for angina pectoris patients, and 15.7+/-9.1 within 6h and 12.5+/-4.6 within 12h after the onset for AMI patients, respectively. The correlation coefficients between hepatocyte growth factor and creatine phosphokinase and between hepatocyte growth factor and CK-MB were 0.68 and 0.74, respectively. The time to reach the maximum (h) and the time to decline to less than half of the maximum level (days) were 6.6+/-2.6 and 1.2 +/-0.2 for hepatocyte growth factor, 19.4+/-8.7 and 2.5+/-1.4 for creatine phosphokinase, and 16.6+/-7.7 and 1.5+/-0.4 for CK-MB, respectively. Hepatocyte growth factor is useful as a prognostic indicator and reflects the clinical course in patients with acute myocardial infarction.