The final checkpoint. Cancer as an adaptive evolutionary mechanism

ABSTRACT

The mechanisms for identification of DNA damage and repair usually manage DNA damage very efficiently. If damaged cells manage to bypass the checkpoints where the integrity of the genome is assessed and the decisions whether to proceed with the cell cycle are made, they may evade the imperative to stop dividing and to die. As a result, cancer may develop. Warding off the potential sequence-altering effects of DNA damage during the life of the individual or the existence span of the species is controlled by a set of larger checkpoints acting on a progressively increasing scale, from systematic removal of damaged cells from the proliferative pool by means of repair of DNA damage/programmed cell death through ageing to, finally, cancer. They serve different purposes and act at different levels of the life cycle, safeguarding the integrity of the genetic backup of the individual, the genetic diversity of the population, and, finally, the survival of the species and of life on Earth. In the light of the theory that cancer is the final checkpoint or the nature's manner to prevent complex organisms from living forever at the expense of genetic stagnation, the eventual failure of modern anti-cancer treatments is only to be expected. Nevertheless, the medicine of today and the near future has enough potential to slow down the progression to terminal cancer so that the life expectancy and the quality of life of cancer-affected individuals may be comparable to those of healthy aged individuals.

KEYWORDS:

• Ageing
• cancer
• cell cycle
• checkpoints
• evolution

Small-scale and large-scale checkpoint events and their rewards

Here life has death for neighbour.

A.C. Swinburne, The Garden of Proserpine (1866)

Cell proliferation is regulated by a complex set of rules and restrictions, with the sole purpose of not letting cells whose DNA has been damaged divide further. The integrity of the cellular DNA is checked and verified at more than one point during the progression into the cell cycle and the type and the quantity of genotoxic damage are differentially assessed so as not to produce mutated cell progeny. This requires extensive control over the progress through the cell cycle, and the result comes at the expense of many cells dying because of failure to comply with the requirements of a certain phase in the cell cycle. Basically, one phase of the cell cycle must be completed before entering the following phase. Failure to prepare for the next cell cycle phase may render the cell unable to progress further until the requirements are fulfilled (e.g. DNA damage is repaired) or may initiate the concerted cascade of events ultimately leading to cell death by apoptosis.

The topological and temporal sites where the mechanisms of surveillance over genomic integrity operate, ensuring that cells could proceed smoothly through mitosis, are often referred to as checkpoint controls. Dividing cells have to be able to pass at least four crucially important checkpoints during different phases of the cell cycle – namely, a G1/S phase checkpoint (often subdivided further into a restriction checkpoint (checks for presence of oncogenic damage) and a competence checkpoint (checks for DNA damage)); the intra-S-phase checkpoint; and the G2 phase and M phase checkpoints, corresponding to each of the cell cycle phases. Not all cell cycle checkpoints are dependent on the presence of DNA damage.[1] The pre-replicative G1/S checkpoints are usually the essential points in which cells stop the progression into the cell cycle. This could happen for a variety of reasons, among which is presence of unrepaired DNA damage; deficit of nucleotide precursors, etc. but it may as well be the need for the cell to exit cell cycling because of terminal differentiation or impending senescence. When the need to halt the progression through the cell cycle arises after the cell is past the G1/S checkpoint, the S phase may be delayed by slowing down the progression of replication forks and delaying the activation of the late replication initiation sites. The intra-S-phase checkpoint is generally independent of DNA damage; rather, it serves to ensure that all DNA is replicated before cell division begins.[2,3] The G2 (topoisomerase II) checkpoint is also considered relatively independent of the presence of DNA damage, as it makes sure that all DNA tangles have been resolved before proceeding to mitosis.[4] The M phase checkpoint is actually comprised of no less than three different checkpoints involved in microtubule formation, assembly of the mitotic spindle and the correct division of sister chromatids between daughter cells.[5–7] It has been demonstrated that the G2 checkpoint, the spindle assembly checkpoint and the mitotic exit checkpoint may act synergistically with earlier checkpoints in conditions of replicative stress, reversing the cell cycle to earlier mitotic phases.[1,8,9] Still, the G1 checkpoints are the essential elements of the mechanisms which do not allow cells with damaged DNA to divide.

What happens, however, if for any reason the G1 checkpoint is passed successfully by a cell that harbours unrepaired or potentially tumorigenic DNA damage? The answer to this question is ‘nothing’, at least in the short term. In the long term, however, accumulation of unrepaired DNA damage or DNA alterations that increase the proliferative potential of the cell may unleash neoplastic growth. This, however, happens usually after years and decades of genotoxic barrage and does not come in leaps and bounds, but, rather, as a long-term consequence of expanding and multiplying errors in DNA that happened many months or years ago. Warding off the potential sequence-modifying consequences of DNA damage during the life of the individual or the existence span of the species is controlled by a set of checkpoints acting on a progressively increasing scale, starting from systematic repair of DNA damage/programmed cell death through ageing to, finally, cancer. They serve different purposes and act at different levels of the life cycle, safeguarding, respectively, the integrity of the genetic backup of the individual, the genetic diversity of the population, and, finally, the survival of the species and of life on Earth as we know it. The defining characteristics of each of these mechanisms are listed below.

DNA repair as an adaptive mechanism

The average eukaryotic cell is subjected daily to a significant amount of genotoxic damage. Only apurination/apyrimidination events amount up to 1000–10,000 hits per mammalian cell per day and the overall damage rate may well reach up to about 10⁶ individual DNA damage events per genome per day.[10,11] The mutation rate of eukaryotic DNA, however, varies between 0.1 and 100 per genome per sexual generation.[12] Obviously, the DNA repair system of the average individual does work remarkably well (with the relatively rare exceptions of inherited DNA repair deficiencies) so as not to allow significant alterations of the genetic content which is to be passed to the progeny of a dividing cell. Generally, the concerted action of base excision repair, nucleotide excision repair, mismatch repair and double-strand break repair, complemented with the ‘SOS-type mechanisms’ of translesion copying are sufficient to carry the individual successfully from conception up to middle adulthood and beyond, after which the risk of somatic mutation resulting in cancer may become significant.

Besides the obligatory pre-replicative check-up of genomic integrity, some types of cells have additional mechanisms for making sure that genetic information is preserved largely unchanged. Some stem cells, for example, among which are neural stem cells, adult muscle satellite cells, etc. employ asymmetric strand distribution during cell division, so that the maternal DNA strand is retained by that daughter cell that is destined to preserve its ‘stemness’ properties, directing the newly replicated DNA (carrying all the potential errors which have occurred during replication) to the daughter cell committed to differentiation.[13–15] Taken together with the fact that stem cells do not divide often but, rather, produce offspring with high proliferative potential which bears the actual burden of replication-associated DNA damage, this seems to ensure sufficiently efficient protection of the stem cell genome so that the resulting cells get a faithful reproduction of the initial genetic blueprint. Not all stem cells, however, use this mechanism of protecting their genome integrity,[16,17] but there are undoubtedly other mechanisms by which the essential tissue-renewing cells protect their genomes against accumulation of errors.

Programmed cell death as an adaptive mechanism

Programmed cell death (apoptosis) serves to remove damaged, infected or transformed cells from the cell population without damaging the neighbouring cells and without triggering tissue regeneration. The decision whether to engage the programmed cell death routine is typically made in the G1/S checkpoint and includes assessment of the scale of the damage. In other words, if the damage is deemed reparable, replication is delayed until the DNA is recovered to a pristine state (or as close to pristine as it could be), or, in cases when the damage is too extensive or too severe, cells are directed to the apoptotic pathway. Different types of damage may have different impact in the assessment of DNA damage, for example, the tolerance of the normal cell to double-stranded breaks is very low, as several of these may render the cell ‘disposable’ while a significant amount of thymine dimers may only result in temporary arrest of the cell cycle.[18] In any case, the decision whether the damaged cell should live or die is taken depending on the individual circumstances by means of a complicated signalling system.[19,20] In the rare cases when the very assessment of the damage is impaired (e.g. inherited ATM (ataxia-telangiectasia mutated) deficiency), cells may not be able to detect small-scale DNA damage and would continue dividing until the level of damage reaches a certain threshold after which the apoptotic induction system is launched. Many modern anti-cancer medications exploit exactly this mechanism of apoptosis induction in cancer cells.[21–23] All in all, cells whose DNA has been damaged get repaired – or end up dead, with special care taken that their DNA is properly destroyed before the cell actually dies. Either way, they are physically eliminated from the cellular pool and their DNA, together with the causative mutations, is made unavailable. We hypothesise that remarkably similar mechanisms operate on a population and supra-population scale. These mechanisms serve to extract ‘damaged’ DNA from the genetic pool so as to ensure that the genetic diversity of the population and the genetic integrity of the species are preserved, respectively. Shocking as it may seem at first, ageing and cancer seem to be key evolution mechanisms similar to DNA repair and apoptosis that protect the life on earth as we know it from being extinguished because of an untimely evolutionary twist.

Ageing and ‘death of old age’ as an adaptive mechanism

The life cycle of higher animals, including humans, usually follows a predefined timeline, which starts with thriving childhood and adolescence, followed by a relatively steady period during which reproduction is ensured and care of the offspring is taken, and, eventually, around the middle age and old age, the population experiences a decline expressed in increase in morbidity and mortality. In old age, the main causes for mortality are vascular disease and cancer and their prevalence seems to increase steadily with advancing age. Research of the causes of death in various age groups shows, however, that in the age group of 75–90, the cancer mortality rises steadily up to 35% as age advances, but after the age of 90, it drops nearly twice, reaching 15%–20% in people aged 95 and over.[24–26] One could speculate that the majority of these oldest elderly may be free of cancer because they had a very effective DNA repair mechanism in the first place, allowing them to promptly repair genotoxic damage before enough sequence errors have accumulated so as to trigger tumorigenesis. Anyone eventually dies, however, so, apparently, apart from accumulating DNA damage, other mechanisms play a role in determining an individual's lifespan, among which natural wear and tear of tissues and organs is prominent.

The natural potential for tissue regeneration is restricted by yet another complicated system for restricting cell proliferation and the lifespan of the cell, namely, the replicative senescence (Hayflick's limit), which coincides with reaching a certain critical length of the telomeres of the cell, beyond which the cell stops dividing and eventually dies. Beyond the embryonic stage, the enzyme activity that restores the length of the telomeres of somatic cells is very low, so eventually all cells in the multicellular organism would enter replicative senescence and die, sooner or later bringing about the end of the organism. In adult life, in virtually every tissue, there persists a small set of cells that serves to replace the lost somatic cells of the tissue, and some types of adult stem cells retain their telomerase activity (e.g. germline cells) or possess the ability to reactivate the telomerase activity.[27] What is more, numerous reports surprisingly identify a positive linkage between advancement of age and the length of telomeres in certain types of cells and tissues. For example, paternal age at the time of birth was found to be associated with longer average length of telomeres in the offspring.[28–30] Also, it has recently been demonstrated that although the telomere length measured in peripheral leukocytes decreases with increasing age, it is not directly related to the mortality rate, especially after the age of 70.[31,32] Therefore, old age is not necessarily linked to loss of ability for tissue renewal as well as of capacity for DNA repair, and the decrease in the regenerative ability is not always associated with a decline, rather, it slows down and settles at a pace optimal for the aged organism.

The tremendous cost of living forever

At least in theory, the natural wear and tear of tissues and organs could be compensated by maintaining and stimulating the adult stem cells' potential for cell proliferation. The question is, what could be gained – speaking purely hypothetically – if constant renewal of aged cells is eventually achieved? Let us imagine a sexually reproducing population of DNA-and-protein-based forms of life with an inherent ability to renew their own cells and tissues. Presumably, so as not to succumb to genetic defects and extreme mutability, they would need to have an extremely high-fidelity system for DNA repair, allowing every cell to pass their DNA intact to their offspring. This would have two immediate consequences, the first being that the population members would have the potential for living for an indefinitely long time, or practically forever – unless a serious injury or some type of severe physical deprivation (air, water, food, etc.) renders them unfit to live. The second consequence would be that they would be able to reproduce from a certain point on practically forever, without ever reaching their equivalent of human age-related hormonal decline/menopause.

If we assume that such a population could exist, and that the environment they live in is relatively stable (e.g. no drastic changes in the climate or in the composition of the air they breathe, etc.), in a relatively short time its descendants would practically crowd the space they live in, and they would eventually die out of lack of resources as no member could die to let other members live. In order to visualize the long-term consequences for our immortal population, however, let us surmise that the resources are abundant and easily accessible, eliminating starvation and/or draught as potential reasons for population extinction.

Some members of this population would, in time, actually die because of physical injury (quite likely, as, since death would be uncommon, the physiological protective mechanism for sensing danger might actually be underdeveloped) leaving the more fortunate members behind. Therefore, after a longer period of time, the population would consist only of descendants of some members of the initial population and not others, which would greatly decrease genetic diversity. This, in turn, would greatly reduce the viability and the adaptability of the offspring (provided that the members of the population reproduce sexually), the end result being that the population that, by definition, had all the potential to live forever would die anyway, especially if the environmental conditions change over time, as the extreme accuracy of repair of DNA would not allow for testing and trying other DNA variants which may be beneficial in a changing environment.

In order to counter the latter potential cause for dying out of our hypothetical population (genetic stagnation), we could presume that our hypothetical beings are capable of introducing some genetic diversity via mutability into their population otherwise threatened by genetic homogeneity – that is, their DNA repair system is not working 100% efficiently. Genetic mutation, however, occurs at random, and therefore, the fortunate individuals who by chance have become carriers of beneficial or indifferent genetic mutations would survive, and the others who are not that lucky, will die. This, however, would lead quickly to reduced genetic diversity once again, as only a small part of the initial population will live and reproduce – even smaller than before, as there would be the added risk of inheriting the same potentially lethal or incapacitating mutation from both parents. Since those individuals who do survive can live practically forever, they will accumulate genetic mutations, henceforth, they would constantly mutate over time and the preservation of the population and the species would be out of the question. It would be highly probable that the different members of the population would become so much different (in genotypic as well as in phenotypic aspects) from one another that sexual reproduction would become difficult or impossible. Moreover, some of these accumulated mutations might have been beneficial in a certain period of time but may eventually become harmful at other times. Let us remember that our hypothetical beings live for a very long time, practically forever, so they would live over climate and geological changes. Thus, a warm hairy hide may help the individual survive a glacial period, but may kill them during a hot and dry spell. Similarly, gills may be helpful in the sea but not on dry earth. Unless our ever-living beings mutate with every change of environment, they are unlikely to survive, despite their potential for everlasting life, or only a few very sturdy, very old, very mutated individuals would survive, but they probably would not be able to reproduce sexually (leaving mutability as the only source of genetic diversity). Their life would not be an example of uneventful evolution, rather, they would be living fossils, defying any evolutionary compromise, existing only by grace of their extreme ability to mutate and renew.

Actually, there are such DNA-and-protein beings living on earth at this very moment, and they look exactly the way one would expect if they have made the taxing evolutionary compromises required to survive. These are some representatives of the phylum Cnidaria, very primitive organisms capable of asexual as well as sexual reproduction, which have branched out of the common evolutionary tree about 550–600 million years ago. Research data corroborating their ability to live for a very long time have been accumulated so far for the genus Hydra, which is capable of extreme regeneration (morphalaxis) and the jellyfish Turritopsis dorhnii (previously known as T. nitricula), which can revert back from mature to immature stage.[33,34] Both belong to class Hydrozoa, but Hydra’s biology is closer to our hypothetical example. The somatic cells of an asexually reproducing polyp of the hermaphroditic hydra are constantly mitotically cycling, old cells sloughing off and being replaced about every 20 days,[35] allowing the individual members to live for a very long time and to regenerate its body even when torn into pieces, unless the whole organism dies for some reason. Hydra's somatic cells can die but they are constantly replaced in order for the multicellular organism to survive; therefore, there is a significant life/death compromise. Even hydras, however, may die for a reason other than severe physical injury. Recently, it has been shown that after sexual differentiation (which may occur in the hydra usually when the environmental conditions are not favourable), the sexually differentiated individuals often experience a decline in their capacity of capturing food, movement and reproduction, and the mortality rate of the population experiences a sharp peak, typical of ageing populations.[36,37] Therefore, the ability to reproduce sexually, that is, to increase genetic variability, comes at the price of the parent individual ageing and eventually dying, but leaving behind progeny with increased genetic diversity, in the hope that the progeny would survive.

Apparently, the ability to repair DNA damage effectively and/or the unfailing ability to produce substitutes to aged or dead cells does not seem to ensure eternal life, except for very primitive organisms who have given up evolution over half a billion years ago. Perhaps this was the period of time when the evolutionary decision to go for increased chances of survival of the offspring via genetic diversity rather than for longer life of the individual via constant renewal of cells and tissues was made, and the hope for eternal life in the biological sense was sacrificed in the name of maintaining life as such.

Ever since the advent of multicellular organisms, individuals are born, grow up, reproduce and eventually die. Death of old age may be well pre-programmed into the life cycle of the individual, and for some species this has been already proved. For example, there are some species of insects currently in existence (e.g. the order Ephemeroptera) in which the adult forms normally die several hours after having become sexually mature and having reproduced, not because of illness or injury, but because of systematic, concerted apoptosis of somatic cells.

Cancer as an adaptive mechanism

How does life turn out, however, for living beings which are, in evolutionary terms, more complex than single-celled organisms and the above-mentioned Cnidaria? They must live long enough to reproduce and, in higher animals and in man, to take care of their offspring so as to ensure the survival and the successful adaptation of the descendants. Then the complex organism will begin to age and would eventually die. Before the latter happens, however, the majority of the individuals in the population would have had the chance to reproduce and, therefore, to contribute to the genetic diversity of the population, while preserving the genetic resources of the species. Ageing, on the one hand, may be viewed as a mechanism to ensure that after they have been given a chance to reproduce, the ‘old’ sources of genetic diversity would be removed from the population, allowing for their offspring to follow in their wake. On the other hand, replicative senescence (which is, for all intents and purposes, the quintessence of ageing) and programmed cell death would ensure that cells that have lived long enough to have been exposed to damaging environmental as well as endogenous mutagenic events would die, so as to avoid the risk of passing altered DNA to the cell's progeny. What happens, however, if and when mutated cells do not die, but continue to proliferate? The biological result is cancer.

A cancerous cell could be described by the famous definition of Siminovich, McCulough and Till [38] as a cell which has the inherent ability to divide in a practically unrestricted manner and to renew its own population. At the time, the definition was proposed for stem cells. Later, the capacity for differentiation had been added to the properties of stem cells so as to distinguish them from immortalized cells and cancer cells. Basically, the potential for proliferation correlates with the malignant potential of the tumour cell, and undifferentiated tumours are much more prone to metastasise than more differentiated cancers. Normal cells may be made to divide beyond the limits of the cell type by undoing the restrictions imposed over the limit of replicative senescence, e.g. by restoring or up-regulating telomerase expression. Still, the programmed cell death mechanism is capable of putting an end to this, and indeed some types of cancer cells may be induced to take the programmed cell death route, while others have disabled this mechanism to ensure sustained proliferation. Disabling the suicide programme may be done by a variety of means, among which is bypassing the checkpoints dependent on DNA damage. Carcinogenesis may also be unleashed by rearrangements in the genome, rendering the normal control mechanisms unusable or ineffective (e.g. up-regulating the expression of pro-proliferative and/or chromatin-modifying transcription factors such as MYC (avian myelocytomatosis viral oncogene homolog), JUN (v-Jun avian sarcoma virus 17 oncogene homolog) or HMGA (high-mobility group A)). Finally, a blockade in the differentiation programme of a cell may result in cancer, as the direct descendants of a stem cell – the transit amplifying cells – usually have high proliferative capacity. All in all, there are many mechanisms to turn a normal cell into a cancer cell, but every single one of these mechanisms does not seem to be enough on its own. There must be a statistical number of events acting simultaneously or consecutively on the same cell so as to ensure cancerous transformation.[39] The DNA repair system seems to deal quite effectively with the potentially mutagenic events which occur every day and the cell cycle checkpoint system equipped with an efficient DNA damage recognition system and a suicide programme seems to be able to resist most of the potentially oncogenic events. Therefore, failure of any of these mechanisms usually occurs only after protracted mutagenic barrage.

The typical phenotype of a malignant cell includes its ability to divide practically indefinitely and to mutate readily, even developing new mechanisms so as to increase the overall mutability. It seems that cancer cells have reinvented the ancient ways for living forever. If we presume for an instant that this could be compatible with the life of the affected individual, we return to the image we described above, namely, genetic stagnation because of selection for the longest-living individuals who, however, bear an enormous mutation burden and are, therefore, unable to sustain the species. With a lifespan that long, and with the random nature of spontaneous mutagenesis, each and every one of these individuals would eventually possess its own unique genotype, which would preclude increasing the genetic diversity by means other than spontaneous mutation, such as sexual reproduction. Again, evolution on such terms would mean the end of life on Earth as we know it. Therefore, one could hypothesise that ageing and death of old age – and when death of old age is not an option, cancer – are the large, population-scale equivalents of the DNA repair/programmed cell death/ageing mechanism, working together to maintain continuation of life by sacrificing individuals in order to preserve the whole. In the physical world we live in, death is the only natural way to extract a damaged cell from its habitat without lasting damage to its neighbours, so that the tissue, the organ and the individual would live. On a larger-scale, death is the only way to sustain life for geological eras without permitting the slow, hit-and-miss evolutionary process to accelerate abnormally and/or go astray. Again, one could hypothesise that ageing is the normal, default process to allow (almost) every population member a chance to reproduce and mix its own genes into the genetic pool, and then to leave the stage for its successors, so that different genetic combinations are tried and tested. Only when cells manage to escape the many complicated mechanisms that order them to age and eventually die, comes cancer, the last checkpoint, and the ultimate fail-safe mechanism which eliminates genotypes that threaten the homeostasis of the population, the species and life as a whole. Certainly, it would be very simplistic if we imagine this as a premeditated event; it is, rather, a naturally occurring phenomenon such as cell division or ageing.

Recapitulation: could cancer be really ‘cured’?

One in six people eventually succumbs to cancer in modern society, despite the advances of modern science and medicine. Why does the united anti-cancer front fail? It looks like cancer cells employ every known trick in the book in order to stay alive, despite the heavy artillery of modern surgery, chemotherapy and radiation treatment.

The flip side of the complexity of the pathways, cascades and checkpoints invented by nature in order to regulate cell proliferation seem to be that, since they can be controlled at many different points, they can also be overridden at many different points and there are shortcuts and workarounds for almost every step in the control of cell differentiation and proliferation. Cancer cells eventually achieve resistance to all currently known chemotherapeutic agents exactly because of the possibilities for regulation at different stages and the alternative biochemical pathways. Moreover, the individual capacity for DNA repair seems to play an important role not only in the probability of developing a tumour (understandably, having a high inherent capacity to repair genotoxic damage does decrease this risk), but also in the chances to benefit from anti-cancer treatment in the case that the tumour has already developed. In the latter situation, cancerous cells with high inherent repair capacity would put up a really good fight against routinely used anti-cancer medications (e.g. platinum derivatives, anthracyclines, bleomycin, etc.), which operate on the basis of creating enough DNA damage for the tumour cell's proliferation to be slowed down and/or the programmed cell death pathway to be activated.[40–42] Some substances which are known to have anti-tumour properties (emodin, curcumin, etc.) actually work exactly by down-regulating the levels of some DNA repair proteins, such as ERCC1,[43,44] allowing treatment-associated DNA damage to accumulate to a level that interferes with the cell cycle of the cancer cell.

The same principle operates when assessing the risk of toxicity related to treatment with some anti-cancer medications. Carrying a polymorphic variant of a gene encoding, a DNA repair protein that decreases the efficiency of DNA repair would certainly increase one's risks of developing a tumour, but after the cancer has already appeared, the same genetic background would allow the DNA-damaging anti-tumour medication to exert its cytotoxic qualities better – with the direct result that healthy cells would be affected as well, producing a phenotype of toxicity. For example, carriership of one of the variants of the above-mentioned ERCC1 gene, 8092A, which increases the chances for successful therapy with cisplatin, increases the treatment-related risk for toxicity as well.[45] Another exemplary case is treatment with erlotinib, in which the clinical success (as measured by patient survival) could be (albeit crudely) assessed by the presence and the severity of erythematous rash: the more severe the rash, the better the patient's outcome.[46,47] Therefore, individual repair capacity is a double-edged sword when it comes to treating cancer.

The first conclusive evidence for the existence of cancer stem cells in 1997 [48] and the resulting research in the field shed some light on the reason why all anti-cancer treatments eventually fail. The concept of cancer stem cells caused an almost complete reversal of the basic paradigms of medical oncology by proposing that tumours have their origins in altered stem cells, and that the treatments killing the rapidly dividing transit amplifying cells would not be effective in the end, as they do not eradicate the tumour source. Existence of cancer stem cells has been definitely proved so far, however, for some cancers only, such as haematological malignancies and some central nervous system tumours, such as gliomas, though conclusive evidence has been accumulating for other types of cancers, too.[49–52] There has been a dispute, however, over whether a ‘cancer-initiating cell’ is the same as a ‘cancer stem cell’ [53] and until the matter has been thoroughly studied, every cancer ought to be and is treated as a separate type, with its own origin, properties and course. It is often the case that different forms of the same basic type of tumour are very dissimilar to one another in respect of their expression profile, aggressiveness, proneness to treatment with various agents, etc. Therefore, a single unifying ‘cancer cure’ does not exist at the moment and is hardly likely to be invented.

Modern biomedical science, in its war on cancer, albeit winning the individual fights, is actually losing the battle in the long run. In the light of the theory that cancer is the final checkpoint, a nature's law that prevents complex living beings from living forever at the expense of genetic stagnation and/or extinction of populations and species, this outcome is not unexpected. Modern medicine, however, has already demonstrated that it may cure completely only some types of cancer and the progression of others may be significantly slowed down so that the life expectancy of cancer-affected individuals may become close to what is seen in normal ageing. In this sense, we are as close as we could ever be to combating cancer.

Conclusions

Eukaryotic cells in multicellular organisms are subjected to significant amount of genotoxic damage. Normally, this damage is rapidly and efficiently repaired. There is, nevertheless, a low but fairly constant error rate of DNA repair that may, with time, result in accumulation of errors in DNA. The efficiency of mechanisms of detection of errors in DNA tends to decline in advanced age, contributing to the rate of accumulation of DNA errors. A cell that has accumulated errors beyond a certain threshold may be forced into replicative senescence or may be redirected to the suicide pathway, so that the errors may not be propagated further. In rare cases when cells manage to abrogate or circumvent the mechanisms that control its proliferation, cancer may develop. Despite the successes of modern medicine, cancer is rarely completely cured and is likely to cause, directly or indirectly, the death of the patient, thereby preventing the propagation of the errors that made the tumour cells capable of avoiding replicative senescence or cell death. Carcinogenesis may be a nature-made mechanism, a kind of a supreme checkpoint to ensure replacement of generations and evolution on planet Earth. Thus, a universal and radical solution to the problem of cancer is unlikely to be developed in the near future. Nevertheless, the medicine of today is already capable of significantly slowing the progression of some types of cancer. It may be expected that the types of treatable cancer would increase so that the life expectancy and the quality of life of cancer-affected individuals may compare to those of healthy aged individuals.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by the National Science Fund at the Ministry of Education and Science of the Republic of Bulgaria [grant number DFNI B01/2].