Introduction
Cancer – although there are over hundred types of it, claims millions of lives every year throughout the world (American Cancer Society, 2007); which is a class of diseases in which a group of cells display uncontrolled growth, invade adjacent tissues and spread to other locations in the body and as a result if not treated in time, leads to death (Pecorino 2008, p.2). On the other hand, Telomeres are repetitive DNA sequences and protein complexes added by an enzyme called telomerase and are located at the end of chromosomes, which stabilises the chromosome and protects it from deterioration. They also have a capping role because telomeres do not perform homologous recombination and prevent non homologous end joining; this is because in contrast to linear DNA, telomeres are structures made up of t-loops and four stranded conformations named G quadruplexes. In mammalian cells, the telomeric sequence is a repetition of a hexanucleotide motif, TTAGGG (Desmaze et al., 2003) varying from 3 to 20 kilobase pairs in length.
Cancer is caused (usually) by abnormalities and/or mutations found in the genetic material of transformed cells (Pecorino 2008, p.4), and as time passes, due to the immense damage caused to the cell's defense mechanisms (e.g. DNA repair), these accumulate. When coupled with environmental factors like poor diet, smoking, stress etc the cells become weaker, quicker; and cancer probability increases in accordance. There are two major types of genes which contribute to carcinogenesis, called oncogenes and tumor suppressor genes. These genes regulate growth and division of cells thus mutations within these genes, cause malfunctioning and abnormal growth of cells which is the foundation of cancer; so one could say cancer is a genetic disease at the cellular level.
Unlike prokaryotes, (most) eukaryotic (this includes humans also) chromosomes are linear which means they have free ends. This detail alone causes problems due to the fact that DNA replication progresses 5' to 3' which leads to discontinuity in the lagging strand, therefore the nucleotide adding enzyme DNA polymerase cannot finish the polymerisation process neatly when it reaches the end of the chromosomes. A small piece of DNA is left unreplicated at the end of each cell cycle which results in that amount of DNA to be lost and if this process carries on the way it does, then this will eventually cause the essential, protein-coding regions of the genome to be lost. This is where Telomeres come into play, since they are at the end of chromosomes and they only consist of non coding regions (in the form of repeats); therefore although some of it is lost, the cell can divide many times before reaching the essential parts of the chromosomes. This problem is not present in (most) prokaryotes because the genome is circular and the end-problem does not occur because there is no lagging strand.
Moving on to humans, it has been observed that somatic cells cease to divide after a limited number of divisions, the number ranging from twenty to ninety depending on the age of the person the cell is being taken from; a phenomenon known as "cellular aging" (Solomonet al. 2002, p.256); for example, cells taken from a 70 year old man can divide 20-30 times compared to one extracted from an infant which can divide 80-90 times (Bodnar et al.,1998). What was observed is that telomeres were much shorter in the older people, and other studies (Cancer Research UK, 2010) also show that as people aged, their risk of being cancer and the percentage of people diagnosed with cancer increased which gave evidence that the two could be linked to one another. Further research into telomere function showed that they had three important functions: Prevent DNAses from degrading the ends of the linear DNA molecules, prevent fusion of the ends with other DNA molecules and facilitate replication of the ends of the linear DNA molecules without loss of essential genetic material (Snustad and Simmons 2006, p.230); and if anything goes wrong with these mechanisms it is highly likely that cancer could progress within the cells where the malfunctioning occurs, so the question is: how does telomeres play a role in cancer development?
Telomeres and Cancer
Approximately 85% of cancers (Pecorino 2008, p.2) occurring in human adults are of epithelial origin, called carcinomas. These tumours have extremely rearranged karyotypes with a high frequency of translocations which are closely linked to cancer development due to the generation of fusion genes, modification of gene copy number and/or deregulation of the expression of several oncogenes. In telomerase knockout mice, telomere shortening below a critical length results in increased end-to-end chromosome fusions which results in dicentric chromosomes and this also generates instability in the genome. These fused chromosomes can break at any random point during anaphase of mitosis and may cause loss of tumour suppressing genes and/or activate oncogenes – which code for products that have the ability of transforming a normal cell in to a cancer cell.
Under normal conditions, telomere shortening only causes limitations to the number of cell divisions. Telomeres protect a cell's chromosomes from fusing with each other or rearranging and can induce replicative senescence which blocks cell division. In normal circumstances cells which have shorter telomeres than the threshold enter a stable and irreversible state of growth and if they evade this stage due to mutations, their telomeres become even shorter, chromosomal instability occurs and tumour suppressing genes are lost, which is recognised by specific mechanisms within the cell and these cells are destroyed by another defence mechanism called apoptosis. Most cancers however, are the result of forever-dividing cells which have ways of evading this programmed destruction. Malignant cells which bypass these mechanisms become "immortalized" by telomere extension mostly due to the activation of telomerase - a reverse transcriptase enzyme responsible for the synthesis/addition of telomeres. Telomerase promotes telomere repair and functions by adding bases (in the form of repeats) to the ends of the telomeres. It is not active in most mammalian cells – only in stem cells, germ cells and hair follicles; but in contrast, is active in 90 percent of cancer cells, thus there is strong evidence that telomerase and telomeres are linked to tumorigenesis. Several oncogenes have also been demonstrated to have a direct link with telomerase. One of them is the transcription factor c-myc, which regulates the expression of the human telomerase reverse transcriptase gene (hTERT) via its promoter region.
The remainder of human cancers activate the Alternative Lengthening of Telomeres (ALT) pathway, which relies on recombination-mediated elongation and does not need telomerase. As human telomeres grow shorter, eventually cells reach the limit of their replicative capacity and progress into senescence. Senescence involves the p53 and pRb pathways and leads to the arrest of cell proliferation and plays an important role in suppression of appearance of cancer (Campisi, 2005). However, by inactivating the p53 and pRb pathways further cell proliferation can be achieved; also cells entering proliferation after inactivation of p53 and pRb pathways undergo abnormal chromosomal rearrangements and leads to genome instability, and (almost) all cells die. Rare cells emerge from crisis immortalized through telomere elongation by either activating telomerase or ALT. The first description of an ALT cell line demonstrated that the telomeres were highly heterogeneous in length and predicted a mechanism involving recombination. ALT cells produce abundant t-circles and if the telomeres become too short, they will (potentially) unfold from their presumed closed structure. The cell turns on certain mechanisms which detects and understands this uncapping as "DNA damage" and then enters cellular senescence, growth arrest or apoptosis, depending on the cell's p53 status. Chromosomal fusions can also result in uncapped telomeres. Since this damage cannot be repaired in normal somatic cells, the cell may even go into apoptosis. Many aging-related diseases are linked to shortened telomeres. Organs deteriorate as more and more of their cells die off or enter cellular senescence – eventually leading to the "inevitable".
Chromosomes that lack telomeres remain unstable until they are capped. Broken chromosomes that do not gain telomeres can undergo sister chromatid fusions involving non homologous end joining. These fusions induce chromosome instability resulting from breakage/fusion/anaphase bridge (B/F/A) cycles. Coming back to the dicentric bridge formed at anaphase (mentioned in introduction), the two centromeres of a dicentric chromosome are pulled towards opposite spindle poles creating an anaphase bridge. The chromosome would then break, resulting in novel chromosomal rearrangements by fusion of broken ends, and perpetuating a B/F/A cycle. Anaphase bridges can also cause whole chromosome losses or the collapse of the cytokinetic process leading to numerical chromosome aberrations. Chromosome rearrangements that can theoretically result from successive B/F/A cycles are similar to those observed in human carcinomas. This process results in highly rearranged chromosomes that eventually acquire a new telomere through gene amplification cycles which is a common consequence of genome instability in tumour cells and can be the basis of oncogene activation and drug resistance.
There is also evidence that chromosomes with shorter telomeres tend to be more affected by radiation; more double strand breaks, deletions and translocations seem to occur in these chromosomes (Desmaze et al., 2003). This phenomenon could also increase the chance of cancer progression as this also can also cause genome instability. All of the above gives strong evidence that telomeres are related with cancer, directly and/or indirectly.
Conclusion
To conclude, excess shortening of telomeres enhances chromosomal instability in cancer cells and the loss of one telomere leads to gene amplification and chromosome imbalances as well as chromosomal instability. Telomeres have important functions in genome stabilisation; and when they are not present or not fully functional there is evidence that these abnormalities – caused due to the shortening or total loss of telomeres, help trigger cancer. Telomeres and cancer are certainly linked but whether telomere shortening is the main cause, the consequence or is involved in (just) one of the steps leading to cancer still needs further research.
In my opinion, (maybe) in the near future, measuring telomerase presence/activity could be considered a new way to detect cancer; also if scientists can learn how to stop telomerase production and/or inhibit its function, they may be able to remove cancer by causing cancer cells to age and die. Also further research into why and how some cancer cells activate the ALT pathway instead of telomerase can also give clues in to how cancer could be treated and possibly lead to development of drug treatments. It is easy to say however, as scientists discover more secrets about telomeres and telomerase, their understanding of cancer will increase in accordance.
References
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About the Author
Mesut Erzurumluoglu
I'm an ordinary guy; and that's all there is to know about me! (show bio)
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