Telomerase Activity and the Risk of Lung Cancer

Telomerase play a key role in the maintenance of telomere length and chromosome integrity. We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Telomerase activity in peripheral blood mononuclear cells was measured by a PCR-designed telomeric repeat amplification protocol in 63 lung cancer patients and 190 healthy controls that were matched for age, gender, and smoking status. Telomerase activity was significantly lower in the lung cancer patients than in controls (mean +/- standard deviation; 1.32 +/- 1.65 vs 2.60 +/- 3.09, P < 1 x 10(-4)). When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (Ptrend = 1 x 10(-4)). Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a significantly increased risk of lung cancer compared to subjects with high telomerase activity (adjusted odds ratio = 3.05, 95% confidence interval = 1.60-5.82, P = 7 x 10-4). These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer.

Does Immunohistochenaical expression of hepatocvte growth factor [HGF] and Telomerase correlate with Ki67 proliferative index in cases of undifferentiated pleomorphic sarcoma [malignant fibrous histiocytoma]?

The latest World Health Organization classification of soft tissue tumors and bone considered MFH a synonym for pleomorphic undifferentiated sarcoma. Hepatocyte growth factor [HGF]/scatter factor [SF] is a cytokine, mainly synthesized by cells of mesenchymal origin acting predominantly on epithelial cells. It has been shown that HGF has proliferative, mitogenic, motogenic, morphogenic and angiogenic activities in various epithelial tissues. Because HGF is ubiquitously expressed in mesenchymal tissues and released to th'e extracellular compartment, paracrine and br autocrine signaling would be a possible mechanism of tumorigenesis in mesenchymal tumors that express the HGF receptor. Telomerase, a highly conserved enzyme, is a specialized cellular reverse transcriptase catalyzing the synthesis and extension of telomeric DNA with its own RNA template. Telomerase compensates for telomere loss due to the end replication problem. Activation of telomerase and stabilization of telomeres are consistent with the hypothesis that telomere maintenance is essential for attainment of immortality in cancer cells. The present study aimed at evaluating and correlating the immunohistochemical expression of HGF, hTERT with ki67 proliferative index in undifferentiated pleomorphic sarcoma [UPS] or malignant fibrous histiocytoma, and investigating their interrelation with some clinicopathological parameters such as age, sex, tumor size, site, and metastases. The present study included 20 cases of undifferentiated pleomorphic sarcoma [UPS] [or storiform-pleomorphic MFH]. They were subjected to immunohistochemical stain using; HGF, hTERT, and Ki67. Positive immunohistochemical expression of HGF was detected in 18 out of 20 studied specimens [90%]. Four specimens [20%] showed 1+ positivity, 5 specimens [25%] showed 2+ positivity and, 9 specimens [45%] showed 3+ positivity. Positive immunohistochemical expression of hTERT was detected in 17 out of 20 studied specimens [85%]. Three specimens [15%] showed 1+positivity, 6 specimens [30%] showed 2+ positivity and, 8 specimens [40%] showed 3+ positivity. Positive immunohistochemica] expression of ki67 was detected in 16 out of 20 studied specimens [80%]. The ki67 proliferative score was as follows: seven specimens [35%] showed 1+ positivity, 4 specimens [20%] showed 2+ positivity and, 5 specimens [25%] showed 3+ positivity. The ki67 proliferative index ranged from 5% up to 90% [mean=40.75%]. The relation between HGF positivity and ki67 proliferative score was statistically significant. [P=0.012]. No statistical significant relation was detected between HGF positivity and hTERT positivity [P=0.225]. Another statistical significant relation was detected between high positivity of hTERT and moderate or high proliferative score of ki67. [2+ or 3+positivity] [P=0.012]. Our findings indicate that the HGF plays an important role in promoting cell proliferation of human MFH tissues. lmmunohistochemical expression of hTERT is considered as a Sensitive marker of malignancy, but its value as a prognostic marker needs further evaluation. Also increased expression of HGF and hTERT were significantly associated with increased ki67 proliferative score

Non small cell lung cancer molecular biomarkers in blood

Several studies have reported significant correlations between individual telomerase activity and apoptosis in malignant tumours including lung cancer. Such studies were carried out on tissue biopsies from the malignant tissue. The aim of the present study was to determine molecular biological parameters that can he used for early biological predisposition for lung cancer. Telomerase activity and Bcl-2 anti-apoptotic protein in circulating lymphocytes, plasma nitric oxide. epidermal growth factor and epidermal growth 'actor receptor were measured in the blood of 25 non small cell lung cancer [NSCLC] patients amid in 20 normal age and socio-economic matching controls, Results revealed significant increase in telomerase activity [53 +/- 8.2 vs. 19.5 +/- 4.8. p<0.0001] between cancer patients and normal controls, significant lower levels of Bcl-2 [7 2 +/- 1,5 vs. 10.4 +/- 1.4 micro g/ml, t 7.3. p<0.0000001] among cancer patients compared to normal controls, However, there were significantly higher levels of epidermal growth factors [6.2 +/- 2 05 vs 0.2 +/- 0.01 pg/ml], epidermal growth factor receptor EGFR [134 +/- 4.7 vs. 102 +/- 2.2 fmol/ml] and plasma nitrate/nitrite [18.8 +/- 4.7 vs. 12.5 +/- 5 micro g/ml. 1=-5.25. p<0.0001] in lung cancer patients compared to controls. This study reveals that Bcl-2 levels in circulating peripheral blood are weak biomarkers for lung cancer, while increase in plasma telomerase activity, NO and EGF levels can he used as reliable biomarkers for cancer prognosis

Prognostic significance of telomerase activity in nasopharyngeal carcinoma

Nasopharyngeal carcinoma [NPC] is one of the very few cancers in which care can be anticipated even in patients with advancer disease. Telomerase enzyme is a specialized multisubunit functioning as a reverse transcriptase that can synthesize the telomeric ends at each cell division. This study aimed to evaluate the clinical significance of telomerase activity, particularly in terms of prognostic impact, in nasopharyngeal carcinoma [NPC]. The studs evaluated 25 NPC specimens using polymerase chain reaction based or telomeric repeat amplification protocol assay. Telomerase activity was detected in 20 [80%] of 25 NPC specimens but in non of the adjacent normal tissue specimens. Factors such as the mean age, sex and size of the tumor did not correlate significantly with telomerase activity. On the other hand, significant positive telomerase activity were observed in the patient with advanced disease, in patients with modal metastases and in patient with poorly differentiated tumour. In conclusion, telomerase activity can be utilized as one of the important prognostic factors in patient with nasopharyngeal carcinoma

Evaluation of E- cadherin and telomerase expression in urothelial carcinoma of the urinary bladder

E-cadherin is a transmembrane glycoprotein involved in intercellular adhesion. A loss or reduction in e-cadherin expression has been linked to the invasive phenotype of a wide variety of human neoplasms. including bladder tumors. Human telomerase reverse transcriptase [hTERT] is a catalytic subunit of telomerase and is a potentially useful diagnostic marker for cancers in many neoplasms, increased telomerase activity is associated with poor clinical outcomes. The objective of the present study was to evaluate the immunohistochemical expression and the potential prognostic value of E-cadherin and telomerase catalytic subunit [hTERT]in urothelial carcinoma of the urinary bladder by comparing them to other prognostic parameters as tumor grade, depth of invasion, and stage. The study comprised 54 patients with bladder tumors who underwent TUR or cystectomy. Formalin fixed paraffin sections from the tumors were processed with a hot, citric acid antigen retrieval method, followed by immunostaining using a monoclonal antibody E-cadherin [NCL-E-cad] Novocastra, mouse monoclonal antibody NCL-L-hTERT [Novovastra]and peroxidase detection system [Novocastra]. Showed loss of normal membrane E-cadherin immunoreactivity in 49 [90.7%] patients. Abnormal expression of E-cadherin was associated with muscle invasive disease [p = 0.0002] and high grade tumors [p = 0.0002].Telomerase [hTERT] was detected in 5 1/54 [94.4%] of urothelial carcinoma, and negative in all normal urothelium adjacent to the neoplasm in cystectomy specimens. No association was found between telomerase and other prognostic factors. In bladder cancer altered E-cadheri n expression is associated with the degree of invasiveness, and tumor grade. However, Telomerase [hTERT] detection by immunostaining is a highly sensitive diagnostic marker for urothelial malignancy but its value as a prognostic marker needs further assessment

Human telomerase reverse transcriptase [hTERT] gene expression in thyroid carcinoma: diagnostic and prognostic role

The catalytic component of telomerase, human telomerase reverse transcriptase [hTERT] has been found to be reactivated in immortalized cell lines and considered as a diagnostic marker for malignancy in different body tissues. Therefore we thought to determine whether hTERT gene detection could serve as an adjunct in the diagnosis of thyroid lesions together with evaluation of its prognostic value. The study included 50 cases of primary thyroid carcinoma including; 28 papillary carcinoma, 14 follicular carcinoma, 5 anaplastic carcinoma and 3 medullary carcinoma in addition to 5 cases of nodular hyperplasia and 5 cases of follicular adenoma. RNA was extracted from paraffin sections of those patients and hTERT gene expression was identified by Reverse Transcription-Polymerase Chain Reaction [RT-PCR]. RT-PCR of hTERT gene revealed expression in 43/50 [86%] malignant thyroid cases; including 25 papillary, 11 follicular, 4 anaplastic and 3 medullary carcinoma cases. On the other hand, hTERT gene expression could not be detected in either hyperplastic nodule or in follicular adenoma cases. The diagnostic validity of hTERT gene detection in benign and malignant thyroid lesions was in the form of 88.3% accuracy, 86% sensitivity, 100% specificity, 100% positive predictive value and 90% negative predictive value. No significant association has been found between hTERT gene expression and any clinicopathologic parameters concerned in this study. In thyroid carcinoma cases, hTERT gene detection was the most independent predictor of poor survival by multivariate survival analysis. Detection of hTERT gene expression should be considered in confirmation of malignant thyroid lesions. Moreover it could be one of the helpful tools in addition to grade, tumor type, and age to stratify patients with thyroid carcinoma into different prognostic categories. Hence, inhibition of hTERT could be of use prospectively in the era of cancer therapy as an attractive weapon in thyroid carcinoma