Telomere Length and Telomerase Activity in Cancer

Telomere Length and Telomerase Activity in CancerConducted on the mean telomere space and the natural action of telomerase in bone marrow samples to bar the survival and chance of B carrell chronic lymphocytic leukemia and erect that the patients with a mean telomere continuance chthonic 6Kb cor associate with high telomerase use similarly the telomere space over 6Kb had a signifi stopt coefficient of correlation with pass up telomerase act (Bechter and Eisterer et al, 1998). This body of work portrays that telomere continuance alone is not sufficient full information to provide prognostic characteristic in genus Cancer therapy only together with the legal action of telomerase it is to a greater extent usable in clinical medicine. elude 2 Mean telomere length and telomerase activity measured and get worded in antithetical types of green goddesscerThe telomere length for about cancers range from very meek to higher than normal bodily cell telomere length. Telomerase activity was alike spy in most cancers except in pediatric bone where trusted types of bone cancers were did not show detectable telomerase activity (Remes and Norrback et al, 2000, Hiyama and Gollahon et al, 1996, Tasumoto and Hiyama et al, 2000, Sotillo-Pineiro and Sierrasesumaga et al, 2004, Sommerfeid and Meeker et al, 1996, Albanell and Engalhardt et al, 1997).However on that point be some problems with this proficiency that makes this topic debatable like for employment to each one type of cancer is unique which make is harder to pick a biological marker that is univers wholey reliable and then the telomerase activity for each type of cancer must be studied soulfulnessly. Another way out is that this system utilize highly sensitive searchs to obtain telomere length and telomerase activity which in return means that it is more susceptible to false substantiating runs or false blackball answers. A false positive result can arise collectible to conta minated lymphocytes as a result of inflammation in the surrounding issues that consume no malignant cancer spread may alike show telomerase activity. To overcome this issue Kinoshita, et al suggested, in a instruction evaluating telomerase activity in bladder cancer, that telomerase assays should be performed after antibiotic treatment. False negative results on the other hand may arise from PCR taq polymerase inhibitors in the sample such as gall salt, heparin and hemoglobin. A highly sensitive telomerase activity assay has been proposed by Yaku and Murashima, et al (2013) that includes the use of magnetic beads which enables the washing subprogram of PCR products to strike any inhibiting contaminants from the samples and hereby limiting the detection of false negative results.What argon the current methods of telomere detection?Table 3 Different technique employ to measure telomere length and their advant yearss and disadvant suppurates.There atomic tour 18 many differen t assays that render been developed to measure the activity of telomerase though the most common method apply is the telomeric tell amplification protocol also known as the snare drum/PCR assay. Although this technique is more sensitive and rapid compared to the conventional assays TRAP assay is not suitable for symptomatic purposes in large clinical samples collectable to its high technicality, obtains clip consuming stages and cannot provide reliable numeric data but many modification of the TRAP assay has been constructed to obtain a better suitable and more efficient way to detect telomerase activity some of which include bioluminescent TRAP-ELIPA (Zu and He et al, 2002), real time quantitative TRAP or (RTQ-TRAP) (Hou and Xu et al, 2001) and the fluorescent TRAP assay (Table 3). On the other hand, several studies have demonstrated enzymatic amplification sooner than PCR based amplification to determine telomerase activity such as the DNAzyme assay (Wang and Donovon et a l, 2013) however although this assay showed higher aesthesia than the TRAP assay, the enzymes utilize in the assay are also prone to crushings by other biological molecules in the sample.A more indirect glide slope in sleuthing telomerase activity has also been carried out by measuring the components of telomerase such as the hTERT mRNA using RTQ-PCR. As the hTR component of telomerase is found in all types of cells whereas hTERT mRNA is only found in cells that express telomerase at that placefore due to the strong correlation between hTERT mRNA levels and telomerase activity it becomes the next example target for detecting telomerase activity and hence cancer. This method was evaluated in peritoneal disseminated cells of gastrointestinal cancers by Botchkina and Rivadeneira et al, (2008) and the study concluded that this method had 100% sensitivity and 100% negative cryive value hence have an authoritative diagnostic value. Furthermore supernumerary pineitudinal studies on larger clinical samples are required to to the full benefit from its clinical cancer diagnostic values nonetheless telomerase activity can be combined with stupefy cytological diagnosis methods to make a more accurate diagnosis. Telomerase activity can also be utilize to detect poor prognosis and friend identify those that have a more advantage of benefiting from jump outive treatments and due to its biological marker properties it can also be useful in the development of anti-cancer therapies.Can telomere length be used to auspicate support prediction?A study conducted on domestic dog breeds show that peripheral blood mononuclear cell telomere length is a strong predictor of average vivification span and the breeds with shorter telomere lengths were found to have an increase probability of deaths caused by cardiovascular diseases. The correlation of telomere length in domestic dogs shows similar telomere biology to homosexuals including telomere length, attrition and absence of embodied cell telomerase activity in comparison to studies conducted in mice models (Fick and Fick et al, 2012). Mice have gnawer telomeres which have a significantly different dynamics in cable to human telomeres and are much longer with shorter animation span, making it unenviable to address whether or not telomere length can be used to predict life expectancy directly. However studies that have been conducted on mice also show that the rate of increasing short telomere length predicts longevity in mammals providing more evidence for the connectedness between telomere length and life expectancy (Vera and Jesus et al, 2012).As telomere shortening is inversely correlated with age which in return is very likely to correlate with age associated issues including lifespan. One of the largest family studies on telomere length in humans also report a correlation between telomere length, aging and life span as well as a significant indication that telomere length is also in fluenced by genetic science specifically from the paternal inheritance (Njajau and Cawthon et al, 2007). This study suggests the possibility that the genes that are dictatorial telomere length may also affect lifespan (Figure 5). Another more recent study conducted by Heidinger and Blount et al, (2011) on Zebra finches, measuring telomere lengths from nesting stage to motley points of its natural lifespan producing the strongest available for the relationship between telomere length and life span. This study suggests that telomere length at early stages in life is a strong indicator of lifespan however as humans detain a higher life expectancy compared to zebra finches its harder to compare these findings to humans. accordingly similar studies should be carried out to evaluate the importance of early life telomere length and lifespan in humans.Figure 5 The mean telomere length in wild type( WT) mice and transgenic telomerase reverse transcriptase (TgTERT) mice both decreased wit h age whereas the amount of short telomeres measured increased with age (5A). This shows that telomere length is significatly negatively correlated with life span in mice similarly to the strong negative association between age and telomere length in humans support by results obtained by Njajou et al (5B).There is a distinct commercialise in the industry that includes various privet companies and clinics such as Life length, RepeatD and TeloMe, which are providing the public the ability to determine an individuals biological age through measuring the length telomeres via blood tests. Most of these companies use flow-PCR, RTQ-PCR or Q-FISH to estimate telomere length however to be able to estimate an individuals life expectancy is a debateable topic however thither are various benefits that comes with obtaining information about how short or long ones telomere is like for example the biological age is an indicator of overall wellness status and essentially help people proceed a he althier life style with better understanding of how life style actions are effect aging process. It is important to take in to consideration that the telomere length tests that are currently available are not able to predict life span as it is effected by a full(a) range of meanss than telomeres alone. Moreover these tests can be used to see if there in an improvement in the rate of biological aging and can even be used to monitor the prognosis of current treatments and help disease opposeion however the uses of these tests in a clinical purlieu still requires further longitudinal research and understanding in more depth of telomeres and its involvement in different diseases than what is currently known. This includes more studies of how telomere length is affected during early stages of life and how the inherited and environmental factors affect telomere length.Is it realistic to alter telomere length using modern technology or in the near future?Table 4 The population doublin gs and telomerase activity detected in pBabe, pBabest2 and pBabest2-AS infected BJ cells.The reconstructions of telomerase activity in normal neonatal human fibroblast cell strain (BJ) which do not poses telomerase activity but however express the RNA subunit of telomerase complex (hTR) have been reported to introduction elongation of telomeres and extend replicative life span. The cells were infected with cDNA coding for hTERT sub-cloned in the retroviral vector pBabe, pBabest-2 and pBabest-2-As. The PBabest-2 under the control promotor of the Maloney Murine leukaemia long terminal repeat sense strand exceeded the normal estimated life span of BJ cells of 87-90 PDs and hence wake evidence for forced expression of telomerase activity results in extended life span (Vaziri and Benchimol et al, 1998). This study reveals that pBabest-2 cells can probablely replace genetically runny cell lines through the expression of telomerase in gene therapy in straddle to treat age related dise ases and cancer.Consequently other studies have shown that the inhibition of telomerase leads to telomere shortening and cell death and therefore can be used as anticancer drugs. Telomerase inhibiting drugs are currently under phase 2 of clinical trials and its effects on telomere shortening is reversible however the process of telomere shortening with inhibition requires a long arrest of time beforehand a significant change in cell growth is seen due to the presence of the cells alternative telomere lengthening mechanisms (ATL) for maintaining telomeres.Figure 6 The HME50-5E cells underwent apoptosis against number of days after transfected with complementary 2-O-MeRNA oligomer telomerase inhibitors. More than 50% of cells went under apoptosis after 100 days after the initial transfection (Herbert et al, 1999).Herbert and Pitts et al, 1999, reported that peptide nucleic acid (PNA) and 2-O-MeRNA oligomers inhibit the activity of hTR telomerase in immortal human cell lines HME50-5E and DU145 hence can be used as a potential chemotherapeutic drug (figure 6). The use of targeting telomerase in direct anticancer therapies also has its drawbacks as telomerase activity is also found in some somatic human cells that may also be targeted during treatment. Additionally a small-scale minority of cancers have been reported to exhibit no significant telomerase activity therefore the treatment may not be as hard-hitting in certain cancers compared to others due to drug resistance. Another issue with this approach is that chemically related molecules may carry the risk if being unexpectedly inhibited which could result in harmful side effects.Based on the research that that has been carried out on telomeres it is well established that telomere length can be easily manipulated however like in most biological pathways when the natural process are disrupted there are ever positive and negative consequence. In this case involuntarily altering telomere length requires the manipulation of telomerase activity (Lee and Hills et al, 2013). The increase in telomerase activity has been associated with multiple different cancers which could therefore potentially increase the risk of developing cancer mend reducing the risk of developing CHD and other diseases that are associated with telomere shortening. Furthermore additional studies are required to develop a more advanced technique that can alter telomere length and at the same time prevent or repress cancer.Alternatively a follow up study reported that a series of lifestyle changes such as mark based diet, moderate exercise, stress management and increased social support provided to men with low risk for prostate cancer, revealed an increase in intercourse telomere length in the intervention group compared to the controls after 5 years. This study shows a significant correlation between telomere length and lifestyle changes, indicating that telomere length can also be altered naturally by reducing th e environmental risk factors associated with telomere shortening without having to interfere with telomerase activity (Ornish and Lin et al, 2013).ConclusionThe denudation of telomeres and telomerase is without a doubt a major revolutionary step in the scientific field which has led to the understanding of biological age and its association with low mortality medical conditions such as CHD and Cancer. However there are still some structural aspects of telomeres and telomerase that are not fully understood, like for example telomere binding factors TRF1 and TRF2 have only a few studies which suggest that they are part of a telomere maintaining control mechanism (Smogorzewska and Steensel et al, 2000). whence these negative regulators can also be possibly targeted in therapies in the future as they have been found to be associated with telomerase activity and hence telomere shortening and eventually lead to programed death of cancerous cells through apoptosis. Although most telomera se inhibition drugs have failed due to long lag phase period before effective shortening of telomeres occur, it can still be used in combination with present chemotherapeutic drugs and provide a more efficiently induced cell death (Cerone and Londono-Vallejo et al, 2006). Moreover telomere length is an supreme biomarker for assessing cardiovascular diseases therefore telomere length testing can be used in clinical medicine as a risk factor for early diagnosis faster than current biomarkers such as cholesterol levels. The future will undoubtedly point to new discoveries of how telomere and age related diseases are associated and help prevent them.