All organisms have a defined size and shape, both at the tissue and cellular level. Almost all types of mammalian cells carry an inbuilt circuit which controls their rate of cell division. This control is vital to maintain the integrity of the cell and the tissue. If cells continue to divide uncontrollably without any intrinsic constraint, tissues can potentially develop to enormous sizes with lethal results for the organism. For example, humans could potentially have massive hearts or enlarged lungs or livers.
Cancer cells are typically defined by their capacity to divide uncontrollably. In order for a clone of cells to expand to the size of a potentially fatal tumour, there must be a disruption in the inherent cellular circuitry controlling cell multiplication. It has long been known that normal mammalian cells grown in a petridish have a finite number of cell divisions. For example, adult fibroblast cells which have been cultured in a petridish in vitro, stop multiplying when the cells reach the edge of the petridish. When a small fraction of these cells are transferred to a new petridish, they start to divide again and so on – a process called passaging. However, after a certain number of transfers, the rate of cell division slows down and ultimately stops below figure.
Leonard Hayflick was the first to demonstrate that cells from rodent or human embryos have a finite number of cell divsions (replicative potential) and he called this senescence. Senescent cells are viable but have lost the capacity for cell cycling and cell division. In a petridish, these cells will take up nutrients and grow (often looking like ‘fried eggs’ because the nucleus and cytoplasm grow in size) but they will not divide. Typically, most normal human cell types have the capacity for 60–70 doublings.
In contrast to normal cells, cultured cancer cells have the capacity to dramatically exceed normal doubling times to almost indefinite levels above figure. A striking example of this is the HeLa cells. Originally cultured from a cervical adenocarcinoma from a cancer patient called Henrietta Lacks in 1951, these cells continue to grow and proliferate in hundreds of laboratories across the world to this day. This clearly suggests that these cancer cells have bypassed/disrupted the senescence regulators within the cell and acquired the capacity for unlimited division (replicative potential).
The cellular mechanism controlling senescence has been discovered in the past 30 years. We now know that the ticking counter which controls finite cell division lies at the end of all human chromosomes – the telomeres. Telomeres are hexanucleotide sequences of DNA (short repeats of 6 base pairs), and each end of a linear chromosome contains thousands of copies of these repeats. For example, in humans the repeat sequence is TTAGGG. These sequences are considered ‘junk’, i.e. they do not code for any proteins. However, they play a vital role in protecting linear chromosomes by preventing end-end fusion and also shield the DNA from degradation by nucleases. The best analogy is that telomeres are like aglets which protect the ends of shoelaces from fraying.
The importance of telomeres in cell division is defi ed by a unique problem of DNA replication called the ‘end replication problem’ below figure. During cell division, DNA replicates during the S phase of the cell cycle creating twice the number of chromosomes. Each set is then divided between each daughter cell at the time of mitosis. However, after every round of DNA replication, a short sequence (50–100 base pairs) of the telomere is lost from the ends of each chromosome. Th s progressive shortening is because the enzyme responsible for DNA synthesis, the DNA polymerase, is unable to replicate the 50–100 base pairs on the end of one strand of the DNA (the 3’ ends). As a result, every round of DNA replication results in the degradation of these sequences and shorter and shorter chromosomes. Since every chromosome has a fi te number of these telomere repeats, successive cycles of replication result in a steady erosion of the telomeres until they cause genetic changes, chromosomal end-end fusions and disarray, and ultimately cell death. Thus, every normal cell has a fi te lifespan, dictated by its length of telomeres.
Cancer cells on the other hand, maintain their telomere lengths without any loss of DNA base pairs. The main strategy used by cancer cells to maintain telomere lengths is by activating an enzyme called telomerase. Almost 85–90% of all cancers have an active telomerase. Telomerases add non-coding, hexanucleotide repeats onto the ends of telomeric DNA, thus maintaining the required lengths above the critical threshold, preventing erosion and allowing unlimited replicative capacity. Unlike cancer cells, actively dividing normal cells have levels of telomerase that are extremely low or undetectable. If telomerase is injected into these cells in vitro, they are transformed into cells that keep dividing limitlessly. Additional evidence on the importance of telomerases in telomere maintenance comes from tumours that have spread to distant locations in the body (metastases) which also show high levels of telomerase expression and activity.
Another interesting feature of telomerases is that they are highly expressed in germ cells (sperm and ova) and embryonic stem cells (ES cells) but gradually diminish during development into adult somatic cells. Cancer stem cells therefore, can be derived from normal stem cells, progenitor cells, or possibly somatic cells and might be immortal, having the capacity of indefinite self-renewal and proliferation.
The evidence listed above suggests that senescence is probably a protective mechanism used by cells to enter a quiescent (G0) phase to escape stress conditions and stop proliferation. Tumours circumvent senescence pathways by activating telomerases and therefore therapeutic strategies aimed at inhibiting telomerases will preferentially kill tumour cells and have no toxicity on normal cells. However, there is some debate that senescence is an artifact of cell culture conditions and not a true representation the phenotype in the body (in vivo). Resolution of this debate will be useful in understanding how replicative potential and tumour progression are linked.
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