**7. Telomeres in prognosis**

It has been suggested that up-regulated expression of telomerase is contributed by the increased copy number of hTERT which was demonstrated by the report that while hTERT protein expression was strongly positive in tumor cells, the expression of hTERT in nonneoplastic mucosal cells as well as stromal elements (except lymphocytes) was weak or negative [80]. In most cases, hTERT expression is closely correlated not only with telomerase activity but also with cancer initiation and progression. In head and neck squamous cell carcinoma and human glioma cell lines, there was decrease in telomerase activity which has been correlated with overexpression of p53, E2F, p16, p21, and p15 individually [81, 82]. In malignant and nonmalignant human hematopoietic cell lines, primary leukemic cells, and normal T lymphocytes, IFN-α is reported to inhibit telomerase activity by suppressing hTERT transcription [83]. In addition to growth and differentiation-related regulation, telomerase activity is subject to regulation by other external and intracellular factors such as UV irradiation [84]. The telomerase having influence over several signaling pathways that determine cell proliferative or death responses when overexpressed might abrogate anti-proliferative or cell death signals. Thus cancer cells with high levels of telomerase might gain a selective growth

Advent of latest cancer biomarkers has increased opportunities for improving cancer diagnostics by enhancing the quickness of detection and efficacy of treatment. In relation to the practice of new therapeutic interventions, proficient biomarkers are helpful in detection and prediction of remission or relapse of cancer at both gross and molecular levels. Telomerase activity is a hallmark of most cancer biopsies, but not generally detected in premalignant lesions and in normal tissue samples except germ cells and hematopoietic stem cells. Thus telomerase activity can be a promising biomarker for diagnosis of malignancies and a target for chemotherapy or gene therapy. Extent of telomerase activity in tumor tissues may be prognostic indicators of patient outcome. Thus, at the present time telomerase is being studied in anticipation of clinical usage. Many clinical trials for telomerase assay in cancer diagnosis are under trial. Fresh or fresh-frozen biopsies, fluids, and secretions are subject for these trials.

Other components of telomerase enzyme complex have also been utilized as biomarkers for telomerase activity. The expression of the RNA subunit of the telomerase complex (hTR) is also regarded as a diagnostic marker [85]. But the expression of hTR does not always correlate with telomerase protein expression in that particular cell type. hTR can be constitutively expressed in certain cell types in which even telomerase activity is not present [86]. Apart from this, mutation in genes of telomerase and associated proteins are considered as a diagnostic and prognostic marker for many genetic abnormalities collectively termed as telomeropathies. Early-onset melanoma tumor syndrome with multiple co-morbid cancers can be predicted from telomerase gene promoter mutation analysis. In this disorder, the mutation in promoter of telomerase gene introduces an erythroblast transformation-specific transcription factor-

binding site, resulting in approximately twofold up-regulation of telomerase [87].

advantage.

**6. Telomerase as biomarker of cancer**

24 Telomere - A Complex End of a Chromosome

Better understanding of telomere structure and its dynamics focused the research on telomeres as biomarkers for several diseases especially in early detection and prognosis of cancers. A reduced telomere length in human hematopoietic tumors predicts a reduced survival time in patients suffering from myeloid leucaemia [94], chronic lymphocytic leucaemia [95], and myelodysplastic syndromes [96]. Although telomere length in solid tumors is suggested as a potential prognostic marker, patient survival rates vary with different cancer types. For example, a short telomere length in prostate cancer correlates with short disease-free interval and shorter overall survival time [97]. Analysis of telomere length of blood cells is also considered as predictive markers for pulmonary and esophageal neoplasia as well as of lymphoma in humans [98]. It has been suggested that the reduced TL in these patients reflects the effects of increased oxidative stress which correlates with cancer risk. Advent of latest technologies to measure relative and absolute telomere lengths has paved the way to use telomere length as diagnostic and prognostic markers. Telomere restriction fragment assay, qFISH, flow FISH, qPCR assay, single telomere length analysis (STELA), and dot-blot telomere assay are the currently available assay methods for telomere length [99].

### **8. Telomerase as drug target**

Telomerase enzyme has recently emerged as an attractive target for cancer as it is a crucial factor required for the tumor immortalization of a subset of cells, including cancer stem cells. Studies have shown that 80–85% of the tumor cells express telomerase, whereas somatic cells lack the expression of telomerase [1]. In the present scenario, the major concern about the chemotherapeutic approaches is the specificity of action and side effects of drugs on normal cells. Difference in telomere length and cell kinetics between normal and cancerous cells shows that targeting telomerase is an effective system to target cancer cells specifically [100]. Although telomerase is not considered as an oncogene, the expression of telomerase is the major reason for the transformation of a normal cell to cancer cell [80]. Compared to most other cancer targets, telomerase antagonists are advantageous due to the wide expression of this enzyme in cancer types [1]. Telomerase also possesses extra telomeric functions which are very crucial for tumor survival and homeostasis [101]. Studies have shown that telomerase-based cancer therapies are less likely to develop resistance against the drugs compared to drugs which target growth factor receptors or signal-transducing enzymes in cancer cells [2]. This ensures that cancer drugs based on telomerase inhibition are non-cytotoxic anticancer approach and have a broad therapeutic value.
