Role Of Telomeres In Progression Of Cancer

All living eukaryotic organisms, the ones that have cells that contain nuclei, include organized structures of DNA and protein, known as chromosomes, where our genetic material is well coiled. At the ends of the chromosomes there are repeated DNA protein sequences that protect their integrity, called telomeres. These play a major role in the development and progression of cancers while their specific sequences allow telomerase, an enzyme that adds sequence repeats in the telomere regions, to bind and lengthen telomeres.

However, this process can lead to cancers, mostly in late stages of life, where cells undergo uncontrolled division. The exact details of how telomeres are involved in such diseases, as cancers, are subsequently discussed.It was back in late 70's; in 1978 when Elisabeth H. Blackburn and Joseph G. Gall were observing the genome of Tetrahymena and discovered that telomeres had a short repeated sequence of these nucleotides: TTGGGG. Human telomeres have a small difference in sequence, TTAGGG (Greider and Blackburn, 2009). They are G-rich repeats where many proteins bind to maintain telomere protection.

TRF2 (telomeric repeat binding factor 2) is essential for the maintenance of telomeres because if this protein is somehow destroyed in the cell, telomeres will be lost at the same time and chromosome ends will be ligated. TRF1 also binds at telomeres and is responsible for their length as well as to make DNA replication through the repeats easier to occur. Both telomeric repeat binding factors interact with other complexes, while the single stranded telomere complex is fundamental in telomerase regulation (Artandi and DePinho, 2009).What really happens with telomeres is that they are vulnerable structures, affected by time because after DNA replication, in every cell division they become shorter. As people age, their telomeres are shorter in comparison to the ones when they were at their early stages of life. This continuous telomere erosion leads to chromosomal instability due to this senescence program, which cells are "doomed̀" to follow.

Apoptosis is the next step and the cell is now at a critical point, while not only ageing but many debilitating diseases as well will become a total thread (Artandi and DePinho, 2009). However, this inevitable thread that we all believe that costs our youth actually happens for protective reasons. This is absolutely true because telomere erosion is an internal clock, showing when a cell is reaching to the end of its life and protecting the cell from tumor developing mechanisms (Shay, 2005). At this point, a sudden overexpression of telomerase reverse transcriptase prevents the senescence stages to be fully completed, thus it prevents cell death. Telomerase lengthens the telomeres before their total erosion.

However multiple mutations might have occurred during the life of a cell and that means that if telomeres become longer after these mutations the genome will be unstable and cells that carry mutations will manage to escape death. These cells are immortal and will become cancerous (Verdun and Karlseder, 2007). An image with all details I have mentioned is shown below.Figure 1.The image shows the two different pathways that a cell can follow during its life. Ageing and cancer are highly linked but again there are opposite processes. Reactivation of telomerase promotes cancer, while prevents ageing (Finkel et al., 2007).

Thus, telomerase combined with these various mutations that promote cell growth and inhibit cell death allow cancer cells to become immortal. They keep dividing, growing and spreading throughout the body sometimes forming tumors (Siegel, 2010). Re-expression of telomerase in cancer cells is what links telomeres with cancer because telomerase is crucial for this continuous cell growth providing telomeres with stability. Many years of research has showed that telomerase is active in almost all tumors related to humans in contrast to normal cells. Telomerase is a ribonucleoprotein enzyme that adds TTAGGG repeats to the ends of chromosomes in order to replace the lost telomeric sequences and improve their genetic integrity.

In addition, telomerase functions by having multiple protein structures which are vital for its activity. What is different from the other polymerases is the fact that contains a single molecule of RNA and this is the key for adding nucleotides to the telomeric ends. Greider and Blackburn refer to its exact role: "Telomerase places the tip of one strand of DNA on the RNA, positioning itself so that the template lies adjacent to that tip.

Then the enzyme adds one DNA nucleotide at a time until a full telomeric subunit is formed. When the subunit is complete, telomerase can attach another by sliding to the new end of the chromosome and repeating the synthetic process" (Greider and Blackburn, 2009). This enzyme is not expressed in somatic cells but only in embryonic and adult male germ line cells, thus it becomes active mostly when humans begin to age (Shay, 2005).Figure 2This image shows how senescence of the aged tissue occurs after time and how tumor can be developed directly from stem cells and mature tissue as well.

Moreover, multiple divisions lead to a premalignant tumor, where there is a chance to defeat cancer because many affected cells undergo in a rapid senescence state and many tumor cells die. However, malignant tumor development occurs when specific mutations in the tumor cells prevent this senescence process to be fully complete, thus the cells continue proliferation and never die (Finkel et al., 2007).However, there are many other researchers who claim the opposite from what is believed. Specifically, they believe, according to their research that people with shorter blood telomeres are more prone to develop cancer.

But other resent studies refute this opinion. Moreover, a trial occurred in 2008 with breast cancer as a subject. Scientists took samples from peripheral blood cells and analyzed the telomeres of 265 female patients who recently developed breast cancer and 446 controls.

The results of the study showed that telomeres of patients with breast cancer were longer than the ones of the control group. Furthermore, short telomere patients showed that they could survive better than patients with long telomeres, thus their length plays an important role in survival and definitely shorter telomeres have a negative effect on this. In addition among the results it was found that from women over 50 years old who suffered from the disease, the ones with shorter telomeres had better results in their treatment because they responded more effectively than women with longer telomeres. All these indicate that telomere connection with cancer is maintained through telomerase, because shorter telomeres show better results in the health of patients in contrast to longer telomeres (Svenson et al., 2008).Moreover, another research that is related to telomeres is done by a group of scientists at the Swiss Institute for Experimental Cancer Research and the University of Pavia.

The results showed that telomeres contain RNA besides DNA. It was generally believed that telomeres were silent, which means that they contain DNA sequences that do not undergo the processes of transcription. But now the new facts reveal the presence of RNA in the telomeres, which are found there not by chance but from transcribed DNA sequences. This is a great discovery because it is related to telomere maintenance by telomerase. Scientists have found that a protein in telomerase regulates the RNA in the telomeres.

If we think about telomerase and how cells become cancerous because of its increasing activity and this affects the RNA, it is true that we might lead to a better understanding of telomerase and maybe cancer therapies are closer now than ever before (Azzalin et al., 2007).A recent discovery, in 2010, was made by researchers of the University of Michigan Comprehensive Cancer Centre on cancer therapy. In the relevant journal published on Science Daily it is mentioned that TRF1 protein is the one that regulates telomerase but Fbx4, another protein, destroys TRF1 leading to an increase in telomeres length. Now another protein called TIN2 has been discovered which binds to TRF1 and prevents Fbx4 from binding to it. It has been found that when both TIN2 and Fbx4 proteins are present the first binds to TRF1 in order to prevent the second to attach to it.

Thus TRF1 is not destroyed and telomere length does not increase, but remains stable. In the light of the discovery of the TIN2 protein scientists are trying to discover a drug that has the same response as TIN2. However, no peptides are found that act with the same way yet, but scientists are getting closer. Lee, a scientist from Howard Hughes Medical Institute refers that if a drug like TIN2 is discovered then telomerase activity will be inhibited, thus we will be able to cure all types of cancer (University of Michigan Health System, 2010, http://www.sciencedaily.com/releases/2010/02/100217074950.htm).Furthermore, many pharmaceutical companies are trying to inhibit telomerase by the use of G4 DNA, which is a guanine-guanine base pairing.

This causes a structural change in the telomeres which leads to a specific modification of the telomeric ends which is not recognisable by telomerase. Thus, it will no longer be able to lengthen the telomeres and if that process stops that means cancer will be avoided. If scientists could stabilise the presence of G4 DNA in cancer cells, these would permanently die because telomerase would be inactive (Neidle, 2009).In conclusion, the role of telomeres in the progression of cancer is directly linked to telomerase activity as the 90% of human cancers need this enzyme in order to continue progression. Telomere lengthening is what causes the disease.

However, multiple researches is done for therapeutic purposes of cancer and scientists are really close to find the drug that will give hope to thousands of people suffering from the disease.

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