Cancer Development In Human Evolution Biology Essay

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Cancer is a natural consequence of human evolution. Cancer development is an evolutionary process within multicellular organism, in simple words more than 100 disease that develop across a time and involve the uncontrolled division of the body's cells. Although cancer can develop in virtually in any part of the body tissue, and each type of cancer has its own unique feature, cancer starts when a cell breaks free from the normal restraints on cell division and begins to follow its won pathway for proliferation, therefore a tumour or mass of cells formed which will start invading the nearby tissues which are termed as invasive cancer or malignant and than these cells can be shed in to the blood or lymph from malignant tumour which establish new tumours called metastases throughout the body in the evolution of cancer the two genes which had been playing a major roles are, in their normal forms, these genes control cell cycle, called proto-oncogenes; encourages cell division, the other category called tumour suppressor genes; inhibits it. the problem rises when proto-oncogenes or tumour suppresser genes are mutated or they turn on to become oncogenes which will stimulate excessive division, here the role of oncogenes which will contribute to the development of cancer, the signal starts with the production of a growth factor a protein that stimulated divisions, this time the protein involved in these growth promoting pathways over actively gives orders to the cell to proliferate much faster than it would, than the role of tumour suppressor genes comes in, a mutation causes such protein to be inactivate or absent and these inhibitory pathways no longer function normally. As other tumour suppressor genes appear to block the flow of signal s through growth-stimulating pathways, therefore the cell continuous dividing and forming a cancer cell, through body back up systems, such as apoptosis; which will prompts a cell to commit suicide, if some essential component is damaged or its control system is deregulated this suggests that tumour arise from cells that have managed to evade such death. One way of avoiding apoptosis involves the p53 protein. This protein only halts cell division, but induces apoptosis in abnormal cells. The second back up system is to limit the number of times a cell can divide and so ensure that cells cannot reproduce endlessly; this system is made up of counting mechanism that involves the DNA segment at the end of chromosome, which is termed as Cellular Senescence. (Hay-flick et al., 1965; Greaves et al., 1996)

The figure below shows how these three parts works together in cancer and cell ageing.

Cellular Senescence is the phenomenon where cells lose the ability to divide. In response to DNA damage (including shortened telomeres) cells either senescence or self-destruct (apoptosis) if the damage cannot be repaired. Cellular senescence appears to be acting as a barrier to cancer, preventing damaged cells from undergoing proliferation. (Vincent et al., 1992)

Organism senescence is the aging of the whole organisms. The term aging has become very commonly lined to senescence. (Vincent et al., 1992)

Cellular senescence is not universal and it is not been observed in signal celled organisms that reproduce through the process of cellular mitosis. Cellular senescence is found to be in sponges, corals and lobsters. In these it had came to notice that cells becomes post-mitotic when they can no longer replicate or double through cellular mitosis for example cells experience replicative senescence. (Vincent et al., 1992)

It is widely believed now that cellular senescence evolved as away to prevent the onset and speared of cancer, p53 is an extraordinary protein whose activities lie at heart of many basic cellular processes, here in this study the role of p53 in cellular senescence, as described 40 years ago by Hay-flick and colleagues described the finite proliferate lifespan, or replicative senescence of normal human cells. (Vincent et al., 1992)

After many decades, research have uncovered the primary mechanism by which replicative senescence occurs ( telomere shortening) as well showing that senescence response is not just limited to replicative, in addition senescence response, is very likely a failsafe mechanism to prevent the proliferation of cells that are at risk, for tumorigenic transformation. In this way there is similarity between senescence and apoptosis but it is different from apoptosis in many respects. (Fledser et al., 2007)

Apoptosis which causes damaged or gives the oncogenic cells to die by orders from different pathways, therefore eliminating them from tissues, where as cellular senescence on the other hand arrested the proliferation of such cells, but does not eliminate them from tissue. As these dissimilarities in both cellular senescence and apoptosis but both are important in suppressing the development of cancer in mammals and both processes are regulated at critical step by p53. (Beitzinger et al., 2006)

Review of cellular senescence

At the start of the assay, a brief review what are facts known so far about cellular senescence, adding to it consequences of it and the latest improvement found under this topic.

Cancer cells must accumulate many mutations before it acquires malignant cells characteristics, each mutation requires at least 20-30 cell divisions. Therefore, it is important to limit the number of available cell division to less than100 would prevent pre malignant cells from divining after accumulating only few mutations and this blocks their progression. Basically this would be the most efficient tumour-prevention strategy would be to have few or no division, but which is clearly incompatible with the growth, maintenance and repair of mechanisms for body to live long. (Koji et al., 2001)

In here comes a senescent cell; a state of cell in which it will not divide again, even in the presence of growth factors, but these cells while not dividing they remain metabolically active and produce many secreted factors, some of which stimulate and others inhibit the growth of tumours.

This cellular arrest of proliferation is accompanied by changes in cell function such as; changes in secretary pathways, expression of proteases, extracellular matrix components and inflammatory cytokines. (Smeal et al., 2007)

To some scientific context, these senescent stromal cells could potentially provide a permissive environment for adjacent per-malignant epithelia cells to survive, migrate and divide. Such alterations in gene expression is senescent cells may change tissue homeostasis and impact on both aging and tumorigenesis in the elderly, declining tissue homeostasis with increasing age, although the presence of telomere shortening which can provide a strong evidence that replicative senescence occurs in vivo, that's what my assay will consider and will elaborate more on the molecular mechanism of cellular senescence. (Jerry et al., 2004)

It was first well documented incidence of cellular senescence was that or replicative senescence; for cultured human fibroblasts, later on many types of mitotically competent cells from a variety of vertebrate species.

There is evidence that replicative senescence of human cells is due to telomere shortening. (Vijji et al., 2007)

The telomere and telomerase connections to aging and cancer

The ends of linear eukaryotic chromosome that contain specialized structures are called telomeres, human telomeres consist of tandem repetitive arrays of the hexameric sequence (TTAGGG), the size of a telomere varies from 15kb at birth to < 5kb some times in a chronic disease states. This mechanism of telomeric repeating itself helps n maintaining chromoscomal integrity and provides a buffer of potentially expendable DNA. The ends of telomeres are protected and regulated by telomere-binding proteins and form a special lariat like structure which is called the t-loop. This package or cap of protection which is found at the end of linear chromosomes is thought to cover or mask telomeres from been recognised or noticed as damaged DNA, therefore protecting chromosome termini from degradation, recombination and end-joining reactions. (Beitzinger et al., 2006; Fledser et al., 2007)

Telomere are composed of arrays of G-rich sequences and telomere-binding proteins, telomeres are synthesized by telomerase enzyme, which is composed of RNA and catalytic protein subunits called (hTERC) and human telomerase reverse transcriptase (hTERT).

The enzyme activity of telomerase hole-enzyme correlates with hTERT expression. In the absence of telomerase activity and (hTERT) expression a state reported for the majority of somatic cells telomeric DNA erodes progressively with each round of cell division and eventually lead cells in to senescence or in to crisis, which result in cell death. Telomerase turns off when undifferentiated progenitor cells in many different self renewing tissues express telomerase activity. (Vincent et al., 1992; Koji et al., 2001)

The inability of DNA polymerase to complete replication of the 3'end of a DNA duplex due to the obligate requirement for an upstream RNA primer, which means in every round or replication the newly synthesized lagging strand is missing the extreme 5'-terminues, which sets up a progressive erosion of telomere sequence, giving 50-200bp per generation in mammalian cells. (Smeal et al., 2007)

The point where the classic state of senescence in normal fibroblasts represents a phenotype in which the cells are proliferatively arrested, these cells remain biochemical active and viable for long periods. This can be termed as programmed aging for example the specific genes which are known to inhibit cell proliferation specially (p21 WAF1) and (p16 INK4a)

To this active process of growth arrest is its abrogation by many DNA tumour virus gene products which target specific cellular regulatory proteins such as tumour suppressor gene products p53 and p105Rb. (Koji et al., 2001)

In human to escape from senescence is only temporary, cells which eventually enter the second state of growth arrest which is termed as crisis, in this case fro example is fibroblasts reached after a further 20-30. (Jerry et al., 2004)

population doublings, in contrast to senescence this is characterised not so much by a fall in birth rate as by increase in death rate, which is accompanished by nuclear pleomorphism and abnormal mitoses. Here the state can be that in crisis it can be interesting convergence of the 'programmed' and 'error theories'. These two senescence and crisis, which the normal cell must over come to escape mortality corresponding to mortality stage 1(M1) and stage 2(M2). (Jerry et al., 2004)

The cell which escapes this process is the stem cells, because these cells express telomerase enzyme which opposes the effect of erosion by making up a new terminal repeat element using an RNA template containing the telomere array sequence. The activity of this enzyme is normally repressed at specific point in embryonic development, after the telomere clock begins to start. (Vincent et al., 1992)

Telomeres and their associated proteins show how preserve chromosome integrity by preventing exonuclease attack by permitting nuclear matrix attachment and perhaps the most important one by preventing end to end fusion. These functions appear to be critically diminished when telomere length falls around 1-2kb, although this probably reflects the near total loss of telomeres from a sub-set chromosome. The observation is that telomere length shortens both in vitro and in vivo as a function of the number of cell doubling. (Jerry et al., 2004)

Two hypotheses have been put forward to explain how telomere attrition might trigger growth arrest in senescent cells. The chromatin conformation mechanisms postulates that telomere erosion exerts as influences on sub telomeric heterochromatin resulting in altered expression, presuming just one or few chromosomes of gene signalling growth arrest. Similar mechanisms which will be based on altered association of telomere binging proteins on eroded telomeres. (Asha et al., 2007)

The other different proposal was that essential trigger result not from the change in the average of telomere length but from a greater degree of erosion occurring in a random sub-set of chromosomes. This is knows that there is an increasing spread of telomere length as cells approach senescence, telomere progressive shortening and changes in gene expression is called position effects (TPE), is dependent on telomere length and is characterized by an all or nothing effect that could be heritable and semi-stable, the concept is when cells have long telomeres, genes near telomeres which might be silenced due to chromatin effects near telomeres, as cells age and telomeres are shorter , there might be some de-repression of genes near telomeres that would lead to reaction pf other previously silenced gene. (Simone et al., 2003)

A number of proteins have been reported to changed in expression level, as a function of replicative age of the cell, as in recent year s several factors other than well knows telomerase regulation pathway which have been to regulate telomere length, considering oxidative damage or mutation of the telomeric DNA, high-order alternative structures, especially the G-quadruplex organised from guanine-rich regions. In recent time a novel gene named regulator of telomere length elongation helicase (RTEL) study carried out by, which encodes a helicase like protein with many other functions, which are shown to help in telomere length regulation in two murine species. The report showed that (RTEL), had removed the harmful structures that would had formed in the G-rich region of genome especially the telomeric DNA, in order to protect the telomere and promote the length balance, as well to that function, it also played an important role in telomere maintenance, embryonic development and increased survival rate in mice. (Zhuo et al., 2007)

Adding to that it also played as a safe guard for the genome, as contribution to the maintenance of genetic stability by reducing unexpected recombination's induced by G-quadruplex. This study was considered as an essential for regulation of telomere length diversity in mammals in general. (Zhuo et al., 2007)

Replicative senescence

Early indications of the importance of p53 in cellular senescence came from studies using the SV40 virus large T antigen, which binds and inactivates both p53 and pRB. T antigen extended the replicative lifespan of cultured human fibroblasts, and also stimulated postmitotic senescent cells to initiate DNA replication. Subsequent experiments used T antigen mutants, the human papilloma virus genes E6 and E7 (which inactivate only p53 or only pRB, respectively), or antisense oligonucleotides to dissect the roles of p53 and pRB in replicative senescence. ( Dasgupta et al., 2006)

Cellular senescence as a tumour suppression mechanism

Cellular senescence is thought to be an important mechanism for suppressing the development of malignant tumours in vivo

The four lines which are supporting this concept are:

Most of malignant tumours contain cells that had over come the limits to proliferation imposed by cellular senescence.

Some viral and cellular oncogenes act as primarily to help cells to overcome senescence

Third the germ line, in which inactivation of certain genes, including p53, resulted in cells that are resistance to senescence induced by proliferation and oncogenes

p53 and pRB, the commonly lost tumour suppressor; functions in human cancer are very important for implementing and maintaining the senescence growth arrest.( Beitzinger et al., 2006)

p53 & cellular senescence:

P53 is also essential for the telomere independent senescence response to DNA damage, oncogenic RAS and over expressed E2F1 as well over expressed p14/ARF and PML. (Jerry et al., 2004)

Human fibroblasts for example that are deficient in p53 function fail to arrest growth and express senescent characteristics when treated agents that induce double stand DNA breaks or oxidative DNA damage, like wise human cell that over express oncogenic RAS or E2F1 or the p14/ARF or PML tumour suppressors fail to undergo a senescence arrest if p53 function is defective, as there is link between RAS and RAF in mitogenic signal transduction, the senescence response to oncogenic RAF is P53-independednt. (Smeal et al., 2007)

Oncogenic RAF may induce cellular senescence by the same mechanism that causes that replicative arrest of p53 deficient cells which minimally entails the activities of p16( but not p21) and pRB. This is done first by the protein kinase which is defective in ataxia telangiectasia (AT) and transmits DNA damage signal to p53, here telomeres end in t-loop; which functions have been already mentioned before hand in the text. This T-loop formation depends on the telomeric DNA binding protein TRF2, if the loss of T-loop, owing to expressing a dominant-negative TRF2, causes tumour cell death by a mechanism that requires both p53 and ATM. This ATM very likely transmits telomere dysfunction signals through p53. (Koji et al., 2001)

How will p53 induce senescence, the study which is carried out recently showed that level of p53 does not appear to increase during replicative senescence, although there is another report to the contrary, in the case of senescence caused by oxidative damage, p53 levels are transiently induced, but later on falls to presenescent levels, p53 levels also increased in response to RAS- and E2F- induced senescence, but it is not known whether the levels eventually decline. It can be possible that p53 is transiently induced during replicative senescence but the induction is un-detectable owing to the fact that replicative senescence is asynchronous, this process does not appear to carry a consistent sustained rise in p53.

Where as on other hand p53 DNA binding activity and transcriptional activity have reported to increase upon replicative senescence, but whether this rise is due to senescence -specific or a characteristic growth arrest is not yet clear. (Simone et al., 2003)

p21, a well recognized p53 target gene, whose rise is noticeable in quiescent and senescent cells, increase to its highest levels in senescent cells. In some light of the possibilities that p53 rises in replicative senescence, it is interesting to see levels of p21 to elevated during the same phase, although p21 levels are elevated is relatively long after human fibroblast cultured reached senescence, p21 levels falls gradually as p16 levels will rise. (Koji et al., 2001)

These findings suggested that p53 initiates the senescence growth arrest at least in part by inducing p21. The subsequent rise in p16 may than act to maintain the senescence growth arrest, p21 also plays a functional role in the changes that occur in senescent cells. Therefore, it is possible that p53 initiates both the senescence growth arrest and some of the functional aspects of the senescent phenotype by inducing p21, whose levels must be sustained at least for several weeks by p53-independent mechanism. (Koji et al., 2001)

The conclusion part from this study showed p53 clearly plays a pivotal role in controlling the senescence response to diverse stimuli. This consistent with the idea that cellular senescence is a tumour suppressive mechanisms and the known role of p53 as a tumour suppressor. (Mingxuan et al., 2007)

Other studied which supported that p53 mechanism is important in vivo, the main object of this study was to examine mechanisms of tumour suppresser induced by short telomeres, mice deficient for the RNA component of telomerase, the report showed short telomeres suppressed tumour function in transgenic mice, as expression of Bcl2 blocked apoptosis in tumour cell, the surprising result showed that mice with short telomeres were still resistant to tumour formation, it was proved by staining the markers for cellular senescence that showed these pretumour cells induced senescence in response to short telomeres, loss of p53 forced the short telomere response, the study provided that in vivo there is existence of p53 mediated senescence mechanism in response to short telomeres that suppresses tumorigenesis. (Fledser et al., 2007)

Even pRB is a crucial gate keeper of cell cycle progression, its activity and its pathway has been illustrated in the figure below, and the new pathway which has been added to it is also shown, the role of p16 INK4a /RB in senescence cell arrest. (Smeal et al., 2003)

Induction of accelerated senescence as anti-cancer therapy

It is clear that the senescence phenotype can be induced under different conditions that might cause impediment to normal mitosis creating a mitotic crisis, including: intrinsic ageing induced senescence (M1); proliferate history dependent telomere attrition induced mitotic crisis (M2); spontaneous, cumulative DNA damage induced senescence; oncogene-induced accelerated senescence; and genotoxin-induced premature senescence. (Roninoson et al., 2003)

Since senescence appears to be a tumour suppressor mechanism, it appears attractive to induce senescence in tumours in vivo in order to create a cytostatic state, where the tumour may not be completely eliminated, but can be maintained in a 'harmless' (non-proliferate) state, Therefore, induction of senescence as an anti-cancer therapy should be approached with caution for the following reasons:

Most of the genotoxins are carcinogens.

Tumour cells already have mutations in the senescent checkpoint pathway. Therefore, the chances of some cells escaping senescence are very high, especially in advanced tumours. ( Roninoson et al., 2003)

Senescent cells secrete factors that can promote tumour progression. ( Roninoson et al., 2003)

Senescent cells facilitate tumorigenesis in adjacent cells. ( Roninoson et al., 2003)

Ageing senescent cells may accumulate additional mutations due to oxidative damage and escape senescent phase via neosis and may result in recurrence of resistant tumour growth ( Roninoson et al., 2003)

Since most anti-cancer chemicals are carcinogenic, and the tumour tissue is a mixture of normal and tumour cells, chemotherapeutic drugs may facilitate tumorigenic transformation of normal or preneoplastic cells. ( Roninoson et al., 2003)

Therefore, the approach of controlling cancer by inducing senescence in vivo, although tempting, may in the long run increase the chances of resistant tumour growth, or facilitate origin of new tumours. One has to better understand the molecular events that regulate senescence and the mode of escape from senescence in tumours, the longevity and fate of senescent cells in vivo, before one can design effective anti-cancer treatment strategies based on senescence. ( Roninoson et al., 2003)

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