Consumer Research Reports, Health & Medicine

Where Does Cancer Come from, and Why has It not Been Eliminated by Evolution?

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Cancer raises a myriad of fascinating questions for biologists, most of them not yet fully answered. How to explain the origins of this disease? Why is she so difficult to treat? Why do vulnerabilities to cancer persist in most multicellular organisms?

Faced with these questions, approaches based on elucidating this disease’s mechanisms and clinical research are not enough. We need to look at cancer from a new perspective, taking an evolutionary view; in other words, we must look at cancer in Charles Darwin’s eyes, the father of evolution theory.

In recent years, the reflections emerging from the mutual consultation of evolutionary biologists and oncologists have led to cross-cutting advances beneficial to both disciplines. They also change our understanding of the disease.

How the evolution of multicellularity sets the stage for cancer

Cancer affects the entire multicellular animal kingdom. And for a good reason: it is an ancestral disease linked to the appearance of metazoans (animals composed of several cells, unlike protozoa made up of a single cell)more than half a billion years ago.

The emergence of such complex organisms has required the establishment of high cooperation levels between the many cells that compose them. This cooperation is indeed underpinned by complementary and altruistic behaviors, in particular apoptosis, in other words, cell suicide (by which a cell triggers its self-destruction in response to a given signal) and the renunciation of direct reproduction for cells other than sex cells. Therefore, the selection makes the evolution of stable multicellularity of adaptations facilitating collective functioning on the one hand and repressing ancestral unicellular reflexes on the other hand.

Cancer represents a breakdown in this multicellular cooperation, followed by the acquisition of adaptations allowing “renegade” cells to improve in their own way of life. In other words, the malignant cells start to “cheat.” They can do this because they have undergone genetic mutations (modification of the sequence of genes) or epigenetic (modifications which change the expression of genes, transmissible but reversible unlike genetic mutations), or even both, which give them greater selective value compared to cells with cooperative behavior. These could be, for example, advantages of growth, multiplication, etc. It is also imperative that the cells carrying these modifications are located in a microenvironment favorable to their proliferation.

If these “cell rebellions” are not properly suppressed by the body’s defense systems (such as the immune system), the abundance of cancer cells may increase locally. Consequences: resources are exhausted, and these cells can then trigger individual or collective behaviors of dispersal and colonization towards new organs, the infamous metastases responsible for the majority of cancer-related deaths.

In a few months or years, a single cancer cell can thus produce a complex and structured (eco) system, the solid tumor, comparable to a functional organ, and more or less disseminated metastases in the body.

An intriguing aspect of this disease is the significant number of similarities between cancer cells’ attributes from different organs, individuals, and even species, suggesting that similar processes take place each time. However, each cancer evolves like a new entity, because apart from the transmissible cancers mentioned above, tumors disappear each time with their hosts, without transmitting their genetic and phenotypic innovations.

How, then, to explain these similarities?

Persistence of cancer through evolutionary time

From an evolutionary point of view, two hypotheses can explain cancers’ appearance and the similarity of their attributes.

The theory of atavism explains cancer by returning to previous cellular capacities, namely the release of a highly conserved survival program, which would still be present in every eukaryotic cell, and therefore in every multicellular organism. This ancestral program would have been selected during the Precambrian period, which began 4.55 billion years ago and ended 540 million years ago. During this period, which saw the emergence of life on our planet, environmental conditions were very different from current conditions and often unfavorable. The selective forces that acted on unicellular organisms promoted adaptations for cell proliferation.

Some of these adaptations, selected during unicellular life, would still be present, more or less buried in our genomes. When their expression escapes the control mechanisms, a struggle between the ancestral unicellular characters and the current multicellular characters ensues, and cancer can then emerge. This hypothesis would also explain why cancer cells adapt very well to acidic and oxygen-poor (“anoxic”) environments because these conditions were frequent in the Precambrian.

The second hypothesis involves a process of somatic selection (somatic cells are all cells other than sex cells), leading to convergent evolution, in other words, to the emergence of analogous characters. This hypothesis suggests that the emergence of cellular characteristics defining “cheating” cells is subjected to strong selection each time a new tumor emerges, regardless of the immediate causes of said characteristics. As these somatic selection processes occur in environments largely governed by the same ecological constraints (such as those prevailing in multicellular organisms’ bodies), they would give rise to convergent evolution.

This explains why we observe similarities across the diversity of cancer. Let us not forget that we only see cancers that succeed in developing: we do not know how many “candidates” fail to acquire the right adaptations at the right times.

These two hypotheses are not mutually exclusive: the re-emergence of an ancestral program can be followed by somatic selection leading to convergent evolution.

Whatever the reason for the origin of cancer, a question arises: since this disease often causes the host’s death, why has natural selection not been more effective in making organisms multicellular fully? Cancer-resistant?

Big animals don’t get cancer anymore.

The mechanisms of cancer suppression are many and complex. Each cell division can cause somatic mutations affecting the genetic pathways controlling cell proliferation, DNA repair, and/or apoptosis, thereby disrupting the control of the cancer-forming process (carcinogenesis).

If each cell division has a given chance that a carcinogenic mutation will occur, then the risk of developing cancer should be a function of the number of cell divisions in an organism’s lifetime. However, large, long-lived species do not have more cancers than small, shorter-lived species.

In natural animal populations, cancer frequency ranges from 0% to 40% for all species sampled and is not related to body massElephants and mice can experience quite similar cancer prevalence levels, although elephants have many more cell divisions in their lifetimes than mice. This phenomenon is called “Peto’s paradox.”

This paradox explains that evolutionary forces have selected more effective defense mechanisms in large animals than in small ones, reducing the burden of cancer as size increases. For example, elephants have twenty copies of the TP53 tumor suppressor gene, while humans have only two.

There are notable exceptions alongside these general trends, for example, with small species with exceptionally long lifespans. These species also have few cancers. A perfect example is that of the naked mole-rat ( Heterocephalus glaber ), a species whose individuals have a long lifespan (long-lived species ) and do not develop spontaneous tumors, except a few cases of detected cancers of anecdotal way.

A disease that occurs late

Let us also remember that anti-cancer defenses’ effectiveness decreases when the organisms have carried out most of their reproduction because the evolutionary pressures are less strong at this stage of life. This drop-in efficiency, coupled with the accumulation of mutations over time, explains why most cancers (breast, prostate, lung, pancreas, etc.) occur in the second part of life.

A major evolutionary implication is that if in “Darwinian” currency, cancer is not a major concern when it occurs after the reproductive phase, it also means that our defenses will have been optimized by natural selection not to eradicate oncogenic processes systematically but to control them as long as we are reproducers …

These “low cost” defenses, which lead to tumors’ tolerance, ultimately prove to be more advantageous for reproductive success than systematic eradication strategies, which would undoubtedly be much more expensive. The immune system, for example, does not work for free … In general, living things are governed by compromises, or “trade-offs” in English, so that any investment in a function corresponds to as many resources and energy that will no longer be available for other functions. Our defenses against diseases, including cancer, are no exception to this operating rule.

Unfortunately, these “low cost” defenses against cancer are ultimately time bombs… Darwinian logic does not always lead to results in line with societal expectations in terms of health!

Although most carcinogenic mutations occur in somatic cells over the course of life, rare cancer cases are caused by inherited mutations in the germline, which produces sex cells. These congenital mutations are sometimes in a frequency higher than what would be predicted by the mutation-selection balance.

Various evolutionary processes can explain this paradox. For example, it has been suggested that natural selection is unlikely to act on these mutations if again their negative health effects occur after the breeding season.

Moreover, the theory of antagonistic pleiotropy could also be invoked. This stipulates that certain genes have opposite effects on the probability of survival/reproduction according to the age considered. These effects would be positive at the beginning of life and negative thereafter. When the positive effect at the start is high, selection may retain this genetic variant, even if it causes fatal disease later.

For example, women with a mutation in the BRCA1 / 2 genes have a significantly higher risk of developing breast or ovarian cancer, but these mutations appear to be correlated with increased fertility.

Implications for treatment

Cancer, a real burden in human populations, is therefore 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. Therefore, the traditional separation between oncology and evolutionary biology must be abolished, as it limits our understanding of the complexity of the processes that lead to the onset of disease.

This new perspective on cancer could prove useful in developing innovative therapeutic solutions that would limit the problems associated with currently available treatment strategies. These high-dose therapies, which aim to kill as many malignant cells as possible, often result in resistant cells’ proliferation. Conversely, adaptive therapy, deeply rooted in evolutionary biology, could constitute an alternative approach.

This strategy reduces the pressure associated with high-dose therapies to eliminate only some of the sensitive cancer cells. In doing so, the objective is to maintain a significant level of competition between sensitive cancer cells and resistant cancer cells to avoid or limit the unconstrained proliferation of resistant ones.

A problem that is not limited to humans

Until recently, oncology had very rarely borrowed concepts from evolutionary biology to improve understanding of malignant processes. Likewise, ecologists and evolutionary biologists have largely ignored the existence of these phenomena in their explorations of life. But things are changing, and the consideration of cancer, or rather oncogenic processes as a whole, within wildlife is generating growing interest within the community of environmentalists and evolutionary biologists.

It is now clear that cancer is both a relevant biological model for studying the evolution of living organisms and an important biological phenomenon for understanding several facets of the ecology of animal species and their consequences on animals’ functioning. Ecosystems.

Even if they do not always progress to invasive/metastatic forms, tumor processes are ubiquitous in metazoa, and theoretical work suggests that they probably influence fundamental variables in ecology, such as the history traits of life, competitive skills, vulnerability to parasites, and predators, or the ability to disperse. These effects come from the pathological consequences of tumors and the costs linked to the defense mechanisms’ functioning in the hosts.

Understanding the ecological and evolutionary consequences of host-tumor interactions has thus become, in recent years, a key research theme in ecology and evolutionary biology.

These scientific questions are all the more legitimate since almost all of the planet’s ecosystems, particularly aquatic environments, are now polluted by anthropogenic origin substances, often mutagenic. Therefore, it is essential to understand better host-tumor interactions and their cascading effects in communities to predict and anticipate the consequences of human activities on ecosystems’ functioning and the maintenance of biodiversity.

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