telomere is the protective dna - protein complex found at the end of eukaryotic chromosome .
telomere dna is made up of repeats of a simple , often g - rich sequence 5ttaggg35 .
telomere shortens upon each cell division due to the dna end replication problem and random breaks produced by free radicals .
the capping function of telomere can also help protect chromosome ends against uncontrolled nucleolytic activity .
excessive telomerase activity is also controlled by the capping function of telomere . the stability of telomere is ensured by the retention of sufficient dna reserves and the activities of numerous protein including the shelterin complex such as telomeric repeat binding factor ( trf1 , trf2 ) , telomere associated protein ( tin2 ) , tripeptidyl peptidase ( tpp1 ) , protector of telomere ( poti ) and repressor activator protein ( rap1 ) . presently , unlike rapi
, the roles played by trf1 , trf2 , tin2 , tpp1 , and poti in mammalian telomere stability has been well established7 .
the role of tpp1 in regulating tert ( telomerase reverse transcriptase ) at the end of chromosome has been well established8 .
it therefore , helps in the formation and protection of telomere and also prevents cells from undergoing senescence910 .
telomerase synthesizes the telomeric dna strand running 5 to 3 towards the distal end of the chromosome thereby extending it .
telomerase activity is commonly found in immortalized carcinoma cells and can also protect cells from apoptotic cell death11 .
the extent to which telomerase activity is regulated in cancer cells is not well known .
telomerase regulates telomere length , thus by changing the level of functional telomerase the length of telomere can be manipulated .
telomerase is made up of three major parts namely , human telomerase reverse transcriptase ( htert)12 , human telomerase rna ( htr)13 and telomerase - associated protein 1 ( tp1 ) and telomerase - associated protein 214 . among these
it , therefore , could serve as a parallel sign in the diagnosis and prognosis of pancreatic as well as other types of cancers .
htert has been discovered to regulate telomerase activity , the expression of the catalytic subunit htert is crucial for telomerase activity15 .
htr has been found to inhibit telomerase activity in tumour leading to telomere length reduction and the senescence of cells .
therefore , detection of htr alone can not play a major role in the diagnosis of pancreatic cancer .
tp1 is also found in both tumour cells and non cancerous cells , and the presence of tp1 does not directly reflect the level of telomerase activity .
telomerase activity is repressed in somatic cells except the haematopoietic progenitor cells , skin basal cells , intestinal stem cells and activated lymphocytes .
imetelstate ( a telomerase inhibitor ) is currently in the phase 1 and phase 2 trials17 .
telomerase activity has been reported to be present in pancreatic juice samples of patients with pancreatic cancer19 . in a study
kim et al21 , facilitated the research on telomerase activity in pancreatic juice of pancreatic cancer patients by the discovery of telomerase repeat amplification protocol ( trap ) and hybridization protection assay ( hpa ) .
trap assay has not yet been applied clinically because of its complexity and its time consuming nature .
c - circle assay ( partially single stranded closed circular dna molecules containing telomeric repeat tracts ) detects higher c - circle ( dna circle ) levels in blood from alt ( alternative lengthening of telomere ) positive patients compared with alt - negative , and may in future be applied clinically for cancer diagnosis22 .
the detection of telomerase subunit htert mrna in pancreatic juice has been seen as a promising diagnostic tool not only for pancreatic cancer but also for other types of cancer23 .
the low level of telomerase activity has also been seen in non malignant pancreatic disorders such as benign adenoma , acute and chronic pancreatitis .
the detection of telomerase activity in pancreatic juice has been found to be a promising diagnostic tool for differentiating between malignant and non malignant intraductal papillary mucinous neoplasm ( ipmn)24 .
this will be a great break - throught because the present diagnostic tools we currently have are not able to distinguish between malignant ipmn and non malignant ipmn .
telomerase activity has been detected in a patient 19 months before he was diagnosed as having pancreatic cancer25 .
telomerase activity examined in both pancreatic cancer specimens and metastasis lesions , showed higher telomerase activity in metastasis lesions than in primary tumours .
it is believed that telomerase activity is directly proportional to the age of the cancer .
the level of telomerase activity in ductal cell carcinoma has been found to be significantly higher in comparison to those in other types of pancreatic cancer27 .
nakashima et al28 did a large scale analysis of 115 pre - operative pancreatic juice specimens to evaluate the feasibility of detection of htert expression by immunohistochemistry for pre - operative diagnosis of pancreatic malignancy , htert expression was detected in 84 per cent of pancreatic ductal adenocarcinomas ( pdacs ) , whereas 62 per cent of pdacs were positive by cytology . when they combined the results of cytology and htert , the sensitivity and overall accuracy increased to 92.0 and 87.8 per cent , respectively .
hashimoto et al29 detected telomerase activity in 83 per cent of patient with invasive ductal adenocarcinomas ( idcs ) while htert was expressed in 88 per cent of idcs .
no significant correlation has been found between the tumour side and the levels of both telomerase activity and htert .
telomerase activity has been detected in bile samples obtained from patients with pancreatic head cancer especially those with obstructive jaundice .
it is believed that bile may inhibit telomerase activity31 , therefore , to detect telomerase activity in bile duct cancers , it is better to detect telomerase activity in tissues .
when telomerase activity was detected in both pancreatic juice and resected pancreatic tissues , it was lower in pancreatic juice than that in resected tissues .
this might be due to the fact that various digestive enzymes found in pancreatic juice , might have intervened in the telomerase assay in inhibiting taq polymerase32 .
it has been proposed that telomerase assays should be used in pre - operative investigation of various malignancies34 .
the detection of telomerase activity in different types of cancer may be helpful in predicting their biologic behaviour36 .
in detecting telomerase activity in pancreatic juice and pancreatic tissues , researchers have encountered problems in obtaining pancreatic juice during operation , or during ercp .
this is an important disadvantage because sample reliability and higher sensitivity and specificity of the assay are key preconditions for its clinical use in the diagnosis of pancreatic cancer .
when normal and cancer tissues are taken for the detection of telomerase activity , sometimes telomerase activities are detected in normal tissues .
sometimes false positive results are obtained due to contaminated lymphocytes which can show telomerase activity without malignant transformation .
kim et al21 detected htert in cd25-positive but not in cd25 negative , peripheral lymphocyte in a normal healthy volunteer .
therefore , in order to avoid the false positive result caused by the contaminated lymphocytes , they suggested the removal of samples exhibiting cd25 expression . also , trap assay is not suitable for clinical use because of its complexity and time consuming factor and also the difficulty in obtaining qualitative and quantitative samples for telomerase analysis .
since telomerase activity is present in a vast majority of human cancers , it may have a clinical application in diagnosing and treating cancers .
the majority of pancreatic cancers shows telomerase activity , consequently , the detection of telomerase activity using a modified trap assay may support a diagnosis of pancreatic cancer .
since c - circle assay is capable of detecting higher levels of c - circles in blood from alt - positive patients compared with alt - negatives , it may in future be applied clinically for cancer diagnosis .
telomerase can be exploited as a target to diagnose and treat cancers because several studies showed telomerase inhibition resulting in telomere instability and cell death3738 .
 pancreatic cancer has one of the worst prognoses among all types of cancers . 
 the survival rate is less than 5 per cent ; this is due to difficulty in diagnosing at an early stage . despite the improvements in diagnostic imaging techniques such as computed tomography , magnetic resonance imaging , etc . 
 , the early diagnosis of pancreatic cancer is still difficult . 
 alternative methods of diagnosing pancreatic cancer at an early stage are presently been explored . 
 the detection of telomerase activity has been proposed to be a useful tool in the diagnosis of pancreatic cancer . 
 telomerase is made up of three major parts namely , human telomerase reverse transcriptase , human telomerase and telomerase -associated protein . 
 several researchers have shown telomerase activity in tissues and fluids of patients with pancreatic and other types of cancers . 
 about 95 per cent telomerase activity has been detected in pancreatic adenocarcinoma . 
 since telomerase activity is present in a vast majority of human cancers , it might have a role in the diagnosis and treatment of cancer . 
Telomere and telomerase
Telomerase activity in pancreatic cancer
Telomerase activity in bile
Telomerase activity in other types of cancer
Problems encountered
Conclusion