Cancer raises a multitude of questions for biologists, many of them still unresolved. How are the origins of this disease explained? Why is it so difficult to cure? Why does vulnerability to cancer persist in most multicellular organisms?
Approaches based on the explanation of the mechanisms of this disease and clinical research are not enough to address these questions.
We must look at cancer from a new perspective, adopting an evolutionary view. In other words, we must look at cancer through the eyes of Charles Darwin, father of the theory of evolution.
For some years, the joint effort of evolutionary biologists and oncologists is fostering reflections that translate into cross-cutting advances beneficial for both disciplines, while changing our understanding of the disease.
How the evolution of multicellular organisms prepares the ground for cancer
Cancer affects the whole multicellular animal kingdom. The reason is that it is an ancestral disease related to the appearance of metazoans (animals composed of several cells, as opposed to protozoa that are constituted by a single cell), more than five hundred million years ago.
The appearance of such complex organisms required the development of high levels of cooperation between the multitude of cells that compose them.
Indeed, this cooperation is sustained by complementary and altruistic behaviors, in particular by apoptosis or cell suicide (by which a cell activates its self-destruction upon receiving a certain signal) and by renouncing direct reproduction by any cell that is not a sex cell.
That is, the evolution towards stable multicellular entities was produced by the selection of adaptations that, p On the one hand, they facilitated collective functioning and, on the other hand, they repressed ancestral unicellular reflexes.
Cancer represents a breakdown of this multicellular cooperation, followed by the acquisition of adaptations that allow these cells to “Renegades” are perfected in their own way of life.
In other words, malignant cells begin to “cheat”.
They can do it because they have suffered genetic mutations (modifications of the sequence of genes) or epigenetic (modifications that change the expression of genes and that, in addition to being transmissible, they are reversible, contrary to genetic mutations), or even both, which gives them a higher selective value compared to cells with cooperative behavior.
It can consist of, for example, in growth and multiplication advantages, etc.
In the same way, it is imperative that cells carrying these modifications nes are located in a microenvironment favorable to their proliferation.
If these “cellular rebellions” are not correctly repressed by the body’s defense systems (such as the immune system), the abundance of cells cancer can increase locally.
Consequences: resources are depleted and these cells can then initiate individual or collective dispersal and colonization behaviors towards new organs, the sadly known metastases responsible for the majority of deaths due to cancer.
Thus, in a few months or years, a single cell cancer can generate a complex and structured “ecosystem”, the solid tumor (comparable to a functional organ), as well as metastases more or less disseminated throughout the body.
An intriguing aspect of this disease resides in the significant number of similarities between the attributes of cancer cells from different organ individuals and even species, which suggests that the processes that take place in each case are similar.
However, each cancer evolves as a new entity, since, apart from transmissible cancers aforementioned, tumors always disappear together with their hosts, without transmitting their genetic or phenotypic innovations.
So, how are these similarities explained?
Persistence of cancer throughout evolutionary time
From an evolutionary point of view, there are two hypotheses that can explain the appearance of cancer and the similarity of its attributes.
The atavism theory explains cancer as a return to previous capacities of cells, among which is the release of an excellently preserved survival program, always present in all cells. Eukaryotic ula and, therefore, in all multicellular organisms.
It is believed that the selection of this ancestral program took place during the Precambrian period, which began 4 years ago. 550 millions of years ago and ended 540 millions of years.
During this period, which saw life emerge on our planet, the environmental conditions were very different from the current ones and, often unfavorable.
The selective forces acting on unicellular organisms favored adaptations for cell proliferation.
Some of these adaptations, selected along unicellular life, were present forever, more or less hidden in our genomes.
When their expression escapes the control mechanisms, a struggle begins between the ancestral unicellular traits and the current multicellular traits and is ento nces when cancer can appear.
Furthermore, this hypothesis could also explain why cancer cells adapt so well to acidic and oxygen-poor (anoxic) environments, since these conditions were common in the Precambrian.
The second hypothesis implies a somatic selection process – somatic cells group all the cells of an organism with the exception of sex cells – which leads to a convergent evolution, that is, to the appearance of analogous traits.
This hypothesis suggests that the appearance of the cellular traits that characterize “tricky” cells undergoes to a strong selection each time a new tumor appears, regardless of the immediate causes of these traits.
These somatic selection processes, taking place in environments governed largely by the same ecological conditioning factors (such as those that prevail inside multicellular organisms es), would lead to a convergent evolution.
That could explain the similarities that we observe across the diversity of cancer. Let’s not forget that we only see cancers that manage to develop, but we do not know how many “candidates” fail by failing to acquire the necessary adaptations at the right time.
These two hypotheses are not mutually exclusive: the reappearance of an ancestral program may be followed by somatic selection culminating in a convergent evolution.
Whatever the reason for the origin of cancer, there is a question that remains unanswered: if this disease usually causes the death of the host, why has it not been more effective is natural selection in making multicellular organisms completely resistant to cancer?
Large animals no longer have cancer
Cancer suppression mechanisms are numerous and complex. Each cell division can cause somatic mutations that alter the genetic mechanisms that control cell proliferation, DNA repair or apoptosis, thus disrupting the control of the cancer formation process (carcinogenesis).
Yes Each cell division carries a given probability of a carcinogenic mutation, so the risk of developing cancer should be a function of the number of cell divisions throughout the life of an organism.
However, large and long-lived species do not have more cancer than small ones that live less time.
In natural animal populations, the frequency of cancer varies, in general, between 0% and 40% for all species studied and there is no relationship with body mass.
Cancer prevalence levels are observed in elephants and mice. They are similar, despite the fact that elephants develop many more cell divisions throughout their lives than mice.
This phenomenon is known as “Peto’s paradox”.
The explanation for this paradox lies in the fact that evolutionary forces have selected more effective defense mechanisms in large animals than in small ones, which allows reducing the burden associated with cancer due to the increase in size.
For example, elephants have twenty copies of the tumor suppressor gene TP 53, while humans only have two.
We found notable exceptions to this general trend, as is the case of small species with unusual longevity. These species also hardly develop cancer.
A good example is that of the naked mole rat ( Heterocephalus glaber ), a species whose individuals live a long time (long-lived species) and do not develop spontaneous tumors, with the exception of some anecdotally detected cancer cases.
A disease that manifests late
Let us also remember that the effectiveness of the defenses against cancer experiences a decrease once that organisms have carried out the essentials of their reproduction, since evolutionary pressures are less at this stage of life.
This loss of efficacy, together with the accumulation of mutations over time , explains that most cancers (breast, prostate, lung, pancreas …) ap appear in the second half of life.
One of the major evolutionary implications is that if, from a Darwinian perspective, cancer is not a relevant concern when it manifests after the reproductive phase, this also means that our defenses will have been optimized by natural selection not to systematically eradicate oncogenic processes but to control them while we have reproductive capacity
In the end , those defenses low cost , whose objective is to resist against to tumors, they turn out to be more advantageous to safeguard reproductive success than as systematic eradication strategies, which would undoubtedly be much more expensive.
The immune system, for example, does not work for nothing …
In general, living beings are governed by compromise solutions, trade-offs in English, which make every investment in a function need a series of resources and energy that will no longer be available for other functions.
Our defenses against diseases, cancer included, are not outside this operating rule.
Unfortunately, those defenses low cost against cancer eventually become lag bombs… In other words, Darwinian logic does not always lead us to results that match our expectations as a society in terms of health!
Although the May r part of cancer mutations occur in somatic cells throughout life, there are rare cases of cancer whose cause is found in hereditary mutations in the germ line, the one that produces sex cells.
These congenital mutations, are sometimes more frequent than would be expected from the mutation-selection equilibrium.
This paradox can be explained by various evolutionary processes. For example, it has been suggested that natural selection will probably not act on these mutations if, once again, their negative health effects only manifest themselves after the reproductive period is over.
By On the other hand, one could resort to the theory of antagonistic pleiotropy. This theory stipulates that certain genes have opposite effects on the probability of survival / reproduction according to the age considered: their effects would be positive at the beginning of life and negative in the rest.
If the initial positive effect Remarkably, it is possible that selection retains that genetic variant even if it causes fatal disease later.
For example, women with a BRCA1 and BRCA2 gene mutation are at significantly higher risk of developing breast or ovarian cancers, but these mutations appear to be related to increased fertility.
Treatment implications
Cancer, the true burden of human populations, is above all a phenomenon governed by evolutionary processes, from its origin in the history of life to its development in real time in a sick person.
The traditional separation between oncology and biology evolutionary evolution, therefore, must disappear, since it limits our understanding of the complexity of the processes that culminate in the manifestation of the disease.
This new perspective on cancer could be useful for the development of innovative therapeutic solutions that limit the problems associated with currently available treatment strategies.
These high-dose therapies, which seek to kill the maximum of malignant cells, often end up causing the proliferation of resistant cells. Conversely, adaptive therapy, deeply rooted in evolutionary biology, could be an alternative approach.
This strategy consists of reducing the pressure associated with high-dose therapies in order to eliminate only a part of the sensitive cancer cells.
The aim is to maintain a sufficient level of competition between the sensitive cancer cells and the resistant cancer cells, in order to prevent or limit the proliferation without restriction of the resistant ones.
A problem that is not limited to the human being
Until recently, oncology had rarely adopted the concepts of evolutionary biology to improve understanding of malignant processes.
Similarly, environmentalists and evolutionary biologists have hardly been interested in the existence of these phenomena in their research on living beings.
But things change and the consideration of cancer – or, rather, of the oncogenic processes as a whole – in the wild fauna arouses a growing enthusiasm within the community of environmentalists and evolutionary biologists.
Indeed, today, cancer is clearly shown as a relevant biological model to study the evolution of living beings, as well as a biological phenomenon of importance to understand various facets of ecology of animal species and their consequences on the functioning of ecosystems.
Although they do not always evolve towards invasive or metastatic forms, tumor processes are omnipresent in metazoans and there are theoretical studies that suggest that, probably , in the latter have influence on fundamental variables in ecology, such as the rasg the history of life, competitive aptitudes, vulnerability to parasites and predators, or even the ability to disperse.
These effects come from both pathological consequences of tumors and costs associated with the functioning of host defense mechanisms.
Understanding the ecological and evolutionary consequences of host-tumor interactions has also become a reference research topic in ecology and biology evolutionary in recent years.
These scientific questions are even more pertinent when practically all of the planet’s ecosystems, especially aquatic environments, are nowadays contaminated by substances of anthropic origin and, often mutagenic.
Therefore, it is essential to improve the understanding of host-tumor interactions and their cascading effects within communities, in order to predict and anticipate the consequences of human activities in the functioning of ecosystems and in the maintenance of biodiversity.
Article translated thanks to the collaboration with Fundación Lilly.
Audrey Arnal is Post-doctorate, at the laboratory MIVEGEC (UMR IRD 224 – CNRS 5290 – Université de Montpellier), Institut de recherche pour le développement (IRD)
Benjamin Roche is Research Director of the Institut de recherche pour le développement (IRD)
Frédéric Thomas is Research Director at CNRS, MIVEGEC laboratory (UMR IRD 224 – CNRS 5290 – Université de Montpellier), Center national de la recherche scientifique (CNRS)
This article was originally published in The Conversation .
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