Cancer and Evolution

Cancer and Evolution

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Edit: just to clarify, I am asking what, if anything, the literature says can be gleaned about evolution by studying cancer, especially relating to how multicellularity evolved and the traits used to force cells under control of the organism.

Most of the original question details I had added were just my own thoughts on the topic.

Original question

Is there a sense in which cancer can be considered as a return to the unicellular "origin" of a cell?

It has always seemed to me like cancer is almost inevitable by the structure of the cell (its poor "design", essentially). The only thing standing in the way are the cellular controls: senescence/apoptosis (e.g. p53 pathway), immunosuppression (e.g. cytotoxic T lymphocytes), telomeres, etc…

So it seems like multi-cellularity did not evolve "ground-up", but was instead generated by slowly differentiating the functions of the various cells, while developing "top-down"controls against errant cellular behaviour. Thus, cancer, which occurs when these protections fail, is in some sense merely a return to an ancient evolutionary root.

I suppose some arguments against this include the fact that modern cells are vastly different than their ancient ancestors (or even modern archaea/bacteria). So the best we can perhaps say is that the core of the cell has been sufficiently preserved (ribosomes are still mostly RNA, are they not? :] ). Further, it is hard to call some of the "micro-evolutions" of cancer (e.g. interleukin-8 production) as returns to primitive behaviour. In these cases, I tend to see them as necessary occurrences to remove the "top-down" controls, rather than as integral to the destructive out-of-control growth characterizing oncogenesis. But, debatably, perhaps not all of them are (e.g. extravasation in metastasis).

Obviously this seems very simplistic, but is there any literature thinking about it this way? Or directly debunking it?

Cancer and level of selection

Cancer results from the opposite action of different level of selection. There is selection on the population of multicellular individuals and there is selection on the population of cells within each multicellular individuals.

There is selection among cells within an individual for increase replication rate while there is selection among multicellular individuals in the population for controlled replication rate of their cells.

Major transitions

The passage from small unit of selection to bigger units is called a "major transition". Such transitions include the grouping of genes on chromosomes, the grouping of cells onto multicellular individuals, the grouping of multicellular individual onto colonies and, if there are several planets inhabiting life in the universe, then the grouping of life forms in every planet into a population of living planets. One can list other, more extreme or intermediate major transitions but there is quite a bit of debate on what really constitute a major transition.

Literature on the subject

[I]s there any literature thinking about it this way?

The keywords that will help search further information are group selection, kin selection, major transitions.

I recommend having a look at Major Transitions In Evolution by Maynard Smith and Szathmary and also The Major Transitions in Evolution Revisited by Calcott and Sterelny which is a book made of many small parts, each written by a different author on these same questions of level of selection.

You might eventually have a look at Evolutionary Dynamics: Exploring the Equations of Life by Nowak as well.

These discussions of level of selection include discussion of what an individual is and what level is most important. The extremely popular and well written books by Dawkins will also bring you some light on the subject. Consider The extended phenotype for example.

For more book recommendations in evolutionary genetics, please have a look at Books on population or evolutionary genetics?.

If you like the sensation of thinking of the entire earth as an individual part of eventually a larger group of living planet, then you'll maybe enjoy having a physiological / ecological view of this living planet earth with Gaia by Lovelock

Cancer and Evolution - Biology

Another perspective on cancer: Evolution within
October 2007

Where's the evolution?
Iconic examples of evolution (birds evolving from dinosaurs, hominids evolving an upright posture, or a lineage of lobe-finned fish evolving four legs and moving onto land) might seem unrelated to the growth of a cancerous tumor, but the process underlying them both — natural selection — is identical. We typically think of natural selection acting among individuals, favoring those carrying advantageous traits and making those traits more common in the next generation. However, the key elements of this process — variation, inheritance, and selective advantage — characterize not just populations of organisms in a particular environment, but also populations of cells within our own bodies. The cells lining your intestines, for example, are not genetically uniform there is variation among them. Some of those cells have incurred chance mutations as they have divided. If one of those mutations (or a series of mutations) allows its bearer to evade cell death and reproduce more prolifically than others, it will pass that mutation on to its daughter cells, and cells bearing that mutation will increase in frequency over time. Like organisms in an ecosystem, cell lineages within one's own body compete for resources. A cell lineage that gains an advantage in that competition, accumulating mutations that allow it to grab extra resources and escape the body's control mechanisms, will proliferate and may evolve into a cancerous tumor.

Though the evolution of a population in an ecosystem and cell lineages in a body rely on the same basic process, there are a few key differences between selection at these different levels. First, whole organisms reproduce much more slowly than individual cells do. This means that while the evolution of a new species or a major transition (such as the evolution of birds from dinosaurs) may take millions of years, the evolution of a cell lineage into a cancerous form can take place on the scale of months or years. Second, natural selection generally increases the evolutionary fitness of individuals, favoring those whose traits allow them to survive and produce more healthy offspring however, selection at lower levels may increase the fitness of cellular lineages at the cost of the individual. In the case of cancer, this is especially obvious: cancerous cells have an advantage in comparison to other cells in the body, but are disadvantageous to the organism. Selection at the cellular level may wind up hampering the organism's survival and reproduction, acting in exact opposition to selection at the individual level.

Why has counteracting these negative effects at the level of the individual (i.e., finding a cure) been so difficult? An evolutionary perspective reveals the answer: cancer — even within one person — isn't a single entity. It's a diverse and evolving population of cell lineages. A single tumor, for example, is made up of a variety of cell types, produced as the cells proliferated and incurred different mutations. All of this diversity means that the population of cells could easily include a mutant variety that happens to be resistant to any individual chemotherapy drug we might administer. To make matters even more difficult, treating the patient with that drug creates an environment in which the few resistant cancer cells have a strong selective advantage in comparison to other cells. Over time, those resistant cells will increase in frequency and continue to evolve. It's not surprising then that a simple cure for cancer has yet to be developed: treating even a single type of cancer is a bit like trying to take aim at a whole set of moving targets all at once.

    Emphasize early detection. The less time that a cancerous cell lineage has to evolve, the less diverse that population of cells will become and, consequently, the easier it will be to target the rogue cells as a group.

Treating cancer means controlling a diverse population of rapidly evolving cell lineages. This challenge helps explain why research has not yet provided us with a cure, but also points the way toward new solutions that take that evolution into account. Research into developing and optimizing these treatments continues, aided by funds generated through events such as National Breast Cancer Awareness Month. Pink sneaker sales and fundraising walks may seem unrelated to evolution, but the cause that they represent is an inherently evolutionary problem.

  • Merlo, L. M. F., Pepper, J. W., Reid, B. J., and Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer 6:924-935.

    from Howard Hughes Medical Institute

Understanding Evolution resources:

Discussion and extension questions

    Describe the basic characteristics necessary for evolution via natural selection to occur.

. The article above describes how natural selection acts on two levels of this hierarchy: populations of organisms and cell lineages. Describe a third level of the hierarchy at which natural selection can act. Explain how that situation meets the criteria necessary for natural selection to occur.

Related lessons and teaching resources

    : In this classroom activity for grades 9-12, students learn why evolution is at the heart of a world health threat by investigating the increasing problem of antibiotic resistance in such menacing diseases as tuberculosis.

: This article for grades 9-12 examines how scientist Andy Ellington has co-opted the power of artificial selection to construct new, useful molecules in his lab. The results of his work could help protect us from terrorist attacks and fight HIV and cancer.

    Greaves, M. (2000). Cancer: The evolutionary legacy. Oxford: Oxford University Press.

Plenary to take closer look at the evolution of cancer biology and therapies

The Tuesday Plenary at the American Association for Cancer Research Annual Meeting 2021 brings together four scientists helping to take cancer therapy in new, exciting directions.

Cancer Biology and the Changing Therapeutic Landscape takes place from 10:45 a.m. – 12:45 p.m. EDT on Tuesday, April 13. Registered attendees can watch a recording of the session through June 21, 2021.

Olufunmilayo I. Olopade, MD, FAACR, University of Chicago Medicine Comprehensive Cancer Center, will explain during “Inherited susceptibility to cancer: From family reunions to the frontline of precision healthcare” how the combination of genomics, artificial intelligence, and deep learning allows for larger worldwide studies finding links for inherited risks and cancer. Olopade’s research involves tracing the root causes of triple-negative breast cancer through study of breast cancer cases in the very young across the African diaspora to understand the genes that may be contributing to inherited breast cancer risk. Study locations include Nigeria, Camaroon, Uganda, Latin America, Brazil, and the United States.

Integrating genomic testing into diagnostic tools can improve health equity by identifying those who are most likely to get cancer at a younger age, aid in prevention for those predisposed to epigenetic cancer variants, and ensure each patient receives the right treatment at the right time, Olopade said.

“We can accelerate how we understand precision health care, where once we were only thinking about the person who has developed cancer, we can now think about the person before they develop cancer and use tools like telehealth, especially after the pandemic, to do comprehensive risk assessment and genomic testing,” Olopade said. “We can now identify the germline variants that can point us toward targeted screening, targeted interventions, and targeted preventions.”

Targeting secreted factors in the tumor microenvironment for pancreatic cancer therapy” will feature Tony Hunter, PhD, FAACR, Salk Institute, reviewing his lab’s work on pancreatic cancer, studying the interactions between tumor and stromal cells that’s leading to the creation of new drugs that target interactions mediated by secreted proteins and other factors. For the past decade, Hunter has focused on the fibroblast-like cells that surround tumor cells with a dense matrix of extracellular proteins such as collagen. These stellate cells also secrete proteins that can act as cytokine growth factors.

“People tend to focus on the tumor cells because they undergo the genetic changes, but they’re supported by and interact with these normal cells,” Hunter said. “The tumor cells are instructing the normal cells what to do, and the normal cells are helping the tumor cells. In some cases, particularly with pancreatic cancer, they’re creating an environment that suppresses the immune response. That’s why pancreatic cancer doesn’t respond checkpoint therapies, to date.”

Hunter’s lab found leukemia inhibitory factor (LIF), a cytokine related to IL-6, made by the stromal cells, promotes chemotherapy resistance in tumor cells, and, in work published in 2019, has shown that a LIF-blocking antibody and gemcitabine increased survival in a mouse pancreatic cancer model. High LIF is also found in human pancreatic cancer tissue, and a phase 1 clinical trial has been completed with a LIF-blocking antibody developed by Northern Biologics.

Dennis J. Slamon, FAACR, Revlon/UCLA Women’s Cancer Research Program at the Johnson Comprehensive Cancer Center, will present “Exploiting cancer biology in developing new treatment paradigms: Examples of past, present and future directions in breast cancer.” Now seen not as a single disease, but as a subtype of molecular diseases, Slamon said, breast cancer has moved beyond the one-size-fits all approaches that previously led to variable outcomes.

William George Kaelin Jr., MD

Slamon will review how the work he, his colleagues and others did led to a new type of targeted treatment using Herceptin for the overexpressed HER2 protein. He also will discuss new pathways that play roles in other subtypes of breast cancer, including CDK4/6 inhibitors, which have dramatically altered outcomes for patients with hormone receptor-positive breast cancers, which accounts for about 65 percent of breast cancer globally. He will conclude with a look at new techniques and technologies that provide increased accuracy in delivering cytotoxic agents to cancer cells while sparing normal cells and new combination therapies as understanding increases about the pathways playing roles in breast cancer pathogenesis.

“We’re looking for changes that aren’t the incremental changes that we used to see with chemotherapy or hormonal therapy regimens,” Slamon said. “We can make large changes and improvements in clinical outcomes, and that’s important as we integrate our understanding of cancer biology into cancer treatment. What we’re looking for is a dramatic improvement in both efficacy and safety, and that’s becoming a reality.”

William George Kaelin Jr., MD, FAACR, Dana-Farber Cancer Institute, will present “(Re)emerging principles of cancer therapy.” Kaelin received the 2019 Nobel Prize in Physiology or Medicine. His laboratory studies the functions of tumor suppressor proteins, using a variety of approaches to understand how these proteins prevent tumor growth.

Pancreatic cancer biology and genetics from an evolutionary perspective

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease. In this Review we gather the wide-ranging aspects of pancreatic cancer research into a single concept rooted in Darwinian evolution, with the goal of identifying novel insights and opportunities for study.


Figure 1. Stages of pancreatic cancer evolution

Figure 1. Stages of pancreatic cancer evolution

Figure 2. Geographic heterogeneity in pancreatic cancer

Figure 2. Geographic heterogeneity in pancreatic cancer

Geographic heterogeneity refers to the spatial variation within…

Figure 3. The three forms of intratumoural…

Figure 3. The three forms of intratumoural heterogeneity within a patient


The origin and subsequent maintenance of sex and recombination are among the most elusive and controversial problems in evolutionary biology. Here, we propose a novel hypothesis, suggesting that sexual reproduction not only evolved to reduce the negative effects of the accumulation of deleterious mutations and processes associated with pathogen and/or parasite resistance but also to prevent invasion by transmissible selfish neoplastic cheater cells, henceforth referred to as transmissible cancer cells. Sexual reproduction permits systematic change of the multicellular organism’s genotype and hence an enhanced detection of transmissible cancer cells by immune system. Given the omnipresence of oncogenic processes in multicellular organisms, together with the fact that transmissible cancer cells can have dramatic effects on their host fitness, our scenario suggests that the benefits of sex and concomitant recombination will be large and permanent, explaining why sexual reproduction is, despite its costs, the dominant mode of reproduction among eukaryotes.

Citation: Thomas F, Madsen T, Giraudeau M, Misse D, Hamede R, Vincze O, et al. (2019) Transmissible cancer and the evolution of sex. PLoS Biol 17(6): e3000275.

Published: June 6, 2019

Copyright: © 2019 Thomas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: FT, RH and BU were supported by the ANR (Blanc project TRANSCAN) and by the CNRS (INEE). OV was supported by the Romanian Ministry of Research and Innovation in the form of an Exploratory Research Grant (PN‐III‐P4‐ID‐PCE‐2016‐0404) and a mobility grant (PN-III-P1-1.1-MC-2018-1986). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: HLA, human leukocyte antigen

Provenance: Not commissioned externally peer reviewed.

One of the greatest enigma in evolutionary biology is the high prevalence (>99%) of sexual reproduction among eukaryotes [1,2]. Because sexual reproduction requires males that do not produce offspring, an asexual population should consequently reproduce faster than a sexual one [3]. Asexual individuals also benefit from maintaining co-adapted gene complexes and avoid costs involved in mate acquisition [4]. Despite this, the high prevalence of sexual reproduction in the natural world indirectly suggests that the selective forces behind the evolution of sex must be strong and pervasive.

Among the most prominent hypotheses that have been put forward to explain the evolution and maintenance of sexual reproduction, the Fisher–Muller hypothesis proposes that sex may rapidly generate multiple novel advantageous alleles [5–7]. Sexual reproduction will also reduce the deleterious effects of Muller’s ratchet, i.e., the build-up and accumulation of deleterious mutations in asexual organisms [8]. Another and probably the most famous hypothesis concerning the benefits of sexual reproduction suggests that recombination create novel genotypes that are able to resist pathogen and/or parasite infections (i.e., the Red Queen hypothesis) thereby maintaining host fitness despite endlessly evolving virulent pathogens/parasites [9,10]. Several empirical studies support this hypothesis [11–13], e.g., in facultative sexual crustacean Daphnia magna, sexually produced offspring were twice as resistant to parasites infecting the parents than asexual ones [14].

All the current hypotheses proposed to explain the evolution of sexual reproduction converge toward the idea that sexual reproduction is beneficial because the genetic diversity it creates provides significant evolutionary advantages to counteract infectious agents, enhance individual intra- and interspecific competition abilities, and alleviate the effects of ongoing fluctuations in environmental conditions [15]. However, what remains unclear is that occasional sex, rather than obligate, could presumably provide the above evolutionary benefits: according to most models, organisms that engage in sexual reproduction only sporadically seem to have the best of both worlds (e.g., [16,17]). Therefore, despite 50 years of research, the selective forces maintaining obligate sex are still not fully understood. Here, we argue that sex has been, and is still, favoured by selection because in contrast to asexual reproduction, it permits to reduce the fitness costs imposed by an ancestral enemy still present: transmissible malignant cell lines.

Multicellular organisms are societies of cooperating clonal cells that have emerged independently on several occasions approximately 1 billion years ago [18,19]. The primary benefit of multicellularity included the division of labor and specialization by differentiated cells [20]. The evolution of multicellular organisms, metazoans, required that individual cells had to forgo their own reproductive interests, i.e., shifting the Darwinian unit of selection from individual cells to the benefit of the entire multicellular community, i.e. the organism. However, one of the first challenges faced by asexual metazoans was, as for any cooperative system (e.g., [21]), the risk of exploitation by internal cheater cells, i.e., cancer cells [22]. Because uncontrolled proliferation of cancer cells is an ubiquitous phenomenon of metazoans [23], it has been proposed to have appeared during the transition from unicellularity to multicellularity [19]. Consequently, the first asexual multicellular organisms did not only have to deal with their own cheater cells but also to evolve adaptations preventing the colonization by infectious malignant cells coming from other individuals. Because anticancer defenses were presumably basic in the first multicellular organisms, both self and infectious cell lines were the major natural enemies. A mile stone in the evolution of metazoans was therefore to counteract and, if possible, to prevent the negative effects of internal cancer cells as well as those caused by non-self invaders, such as viruses, bacteria, parasites, as well as somatic and germ cell parasitism (e.g., in ascidians [24–26]) as well as transmissible cancer cells. These interactions ultimately resulted in the evolution of different evolved defense mechanisms (e.g., different branches and aspects of the immune system) across the animal kingdom. However, in order to reduce the deleterious effects of transmissible cancer cells, the metazoan immune system had to acquire an ability to differentiate between the former and healthy somatic cells.

While the ultimate fate of the vast majority of present malignant cancer cells is to perish with the death of their host, transmissible cancer cells have during the last decades been shown to occur in both invertebrates and vertebrates, often resulting in a massive increase of host mortality (reviewed in [27]). This transmission can involve direct routes such as interindividual aggression (e.g., biting), sexual interactions, and passive transport of transmissible cancer cells. The ability of some of these transmissible cancer cells to avoid immune recognition appears to emanate from a combination of reduced host genetic diversity (that could be the result of bottlenecks and small effective population size [28]) and an ability of the transmissible cancer to down-regulate their antigenic epitopes [27]. Other albeit rare transmissions of cancer cells have been observed in humans from mother to fetus [29,30], i.e., in which the maternally derived neoplastic cells in the infant had deleted human leukocyte antigen (HLA) alleles suggesting a possible mechanism for immune evasion [30]. Moreover, neoplastic leukemia cells arising in one monozygotic twin, having a single or monochorionic placenta, have been shown to transmit to the co-twin via intraplacental anastomoses [31,32], highlighting the impact of genetic similarity in the successful transmission of cancerous cells. Other organisms, such as the basal metazoan hydra, when reproducing asexually have also shown occurrence of vertical interindividual transmission of tumors [33].

Because clonal reproduction leads to organisms that are identical, we propose that (1) malignant cells produced by the first multicellular organisms were likely to be well adapted to other (identical) organisms, including direct descendants (2) it was difficult for the victim organisms to recognize (and hence eliminate) transmissible cancer cells that were almost identical to normal somatic cells (i.e., immune evasion). An efficient way to prevent this was to be different from other individuals, and also to produce unique offspring. Organisms adopting sexual reproduction, conversely to clonal ones, form gametes, mix those together, and create progeny with an entirely novel genome. This both limits the chance for clonal infectious malignant cell lines to be already adapted to a novel host and increase the chance that victim organisms can immediately detect the colonization by a transmissible malignant cell, i.e., malignant cells are this time perceived as foreign allograft. Therefore, sexual reproduction could have evolved as an adaptive trait to prevent horizontal and/or vertical transmission of cancer cells (Fig 1).

(A) Asexual reproduction maintains high levels of interindividual similarity within a population, and this phenomenon increases the risk of vertical and horizontal transmission of malignant cells. (B) By blending genetics, sexual reproduction produces greater genetic diversity in a population, and as such, limits the transmission of cancer cells across individuals in the population. Genetic diversity facilitates the detection of the invading non-self cells and also limits the chances that the transmissible cancer cells are preadapted to the new host. Thus, cancer cells regularly emerge (e.g., red tumor) in individuals, but unless a “perfect storm” is present, as in the Tasmania devil/devil facial tumor disease system [27], malignant cells fail to be transmitted.

If the transmission of cancerous cells was a major factor in the evolution of sexual reproduction, the negative effects of such cheaters may also affect “super organisms,” such as social insect colonies, the queen being the gonads, the workers being the somatic cells, a system comparable to that of a multicellular organism [34]. Some social asexual ants and honey bees do develop asexual cheater workers that abandon reproductive self-restraint and reproduce at the expense of other colonies, hence adopting a behavior comparable to selfish transmissible cheater cells in a multicellular organism [35,36]. Moreover, analogous to transmissible cancerous cells, these cheater workers often invade other colonies with devastating consequences for the colony [35,36]. Just like host defense mechanisms (i.e., immune responses), the colonies of superorganisms police against the cheater workers, whereby the queen and/or the workers inhibit the reproduction of cheaters, by either attacking and mutilating recalcitrant workers or by consuming their eggs [37,38].

Empirical testing of theories that explain the evolutionary origin(s) of sex is often complex. However, several observations seem to support our hypothesis:

  1. Although sexual processes undoubtedly antedated multicellularity, no successful transition to multicellularity (i.e., when cancer emerged [33]) has avoided a tight connection with the sexual process [39,40]. Multicellularity may even set the stage for the overall diversity of sexual complexity throughout the Tree of Life [41].
  2. Species that are not affected by cancer, like prokaryotes and unicellular eukaryotes, should intermittently revert to asexual reproduction. Accordingly, bacteria and archaea reproduce primarily through asexual reproduction, usually by binary fission, with some genetic exchange and recombination occurring occasionally through horizontal gene transfer [42]. The majority of protists and fungi reproduce asexually via fissioning, budding, or spore production [43].
  3. Unlike animals, plants rarely develop cancer, potentially due to fundamental differences between plant and animal cellular structures, development, and physiology (reviewed in [44]). Plant cells possess rigid cell walls (containing hemicellulose fibers, pectin polysaccharides, and lignin) that maintain strict cellular structure and prevent uncontrolled cell growth. Plant cells also rarely accumulate enough mutations that would lead to cancer, due to their stem cells being hypersensitive to DNA damage and being ready for apoptosis in response to genetic abnormalities. The locomotion of tumor cells is also limited because plants rely on an acellular vascular system (i.e., the xylem and phloem), not on cellular circulatory systems such as blood or lymph vessels. Although plants can occasionally develop tumors, they occur much less often than in animals they are not metastatic and certainly not as lethal [44,45]. Although plant reproductive strategies are highly diverse [46], many plants exhibit dual reproductive modes, producing both sexual and asexual offspring, being capable of vegetative reproduction (via rhizomes, runners, tubers, bulbils, etc.) and/or of asexual seed production [47,48].
  4. According to our theory, most asexual species should have a recent evolutionary history, whereas ancient asexual species should possess special adaptations to reduce the deleterious effects of cancer. Close to 50% of asexual lineages have been estimated to be <500,000 years old [49], whereas the remaining 50% of lineages consist of the “evolutionarily scandalous” organisms, such as orbatid mites, darwinulid ostracods, and bdelliod rotifers, that have persisted for millions of generations [49]. The latter species have indeed been shown to be resistant to mutagens such as radiation and heavy metals [50–53], which indicates high resistance to oncogenic processes and selection of tumor-suppressor mechanisms that enable the survival of these ancient asexual lineages.
    As a corollary, one might predict that recently evolved asexual species should be affected by cancer at higher frequency than their sexual conspecifics, unless they also have evolved efficient anticancer defenses. Further studies would be necessary to test these hypotheses.
  5. Multicellular eukaryotes that are strongly impacted by malignant cell emergence and proliferation should mostly have obligate sexual reproduction. Obligate sex is indeed the dominant mode of reproduction in many lineages of complex eukaryotes [1].
  6. Transmissible cancers should be rare in species practising sexual reproduction. Although we probably underestimate their prevalence [54], only 4 cases of transmissible cancers are currently known in the wild, supporting the idea that the evolution of transmissible cancer in sexually reproducing species is very rare and occurs only under very particular conditions (e.g., the “perfect storm hypothesis” [27]).

There are different possibilities to experimentally test our hypothesis. For instance, we predict that in organisms reproducing both by sexually and asexually, a shift toward more sexual reproduction should be observed following the emergence and progression of malignant cells. Hydra has the ability to switch between sexual and asexual reproduction and the propensity to develop tumors, therefore it could be a good candidate to test this hypothesis [33]. In accordance with our hypothesis, parental tumors are almost systematically transmitted to daughter polyps of hydra when reproduction is asexual (i.e., budding results in the vertical transmission of tumors), whereas offspring resulting from sexual reproduction are tumor free [33]. Demonstrating that tumor-bearing hydra, compared with healthy ones, preferentially reproduce sexually would provide support to our hypothesis. Because tumors can also be experimentally transplanted between polyps, this biological system also offers the possibility to test whether transplanted tumors establish better when recipient polyps are identical to the donor with tumors, compared with when they are different individuals.

Constant progress in animal cloning [55] could also help to evaluate the risk of cancer cell transmission associated with asexual reproduction. We predict that the likelihood of mother to fetus malignant cell transmission will be higher when the implanted embryos (e.g., in mammals) are genetically identical to their mother, compared with embryos that have originated form another female or are the mother’s natural embryos.

Comparative oncology approaches could also provide in depth analyses of the difference in anticancer defenses between recent and ancient asexual species, as well as in comparison with their sexual relatives. From a theoretical perspective, our hypothesis could be tested through developing new theoretical frameworks based on mathematical models so far used to elucidate the “Red Queen” hypothesis [56,57]. However, current mathematical models applied to host–pathogen interactions rarely consider parasite diversity. In the case of our hypothesis, future theoretical extensions will need to consider the fact that host diversity generated by sexual reproduction decreases the probability of cancer cell transmission and thus de facto reduces the diversity of the cancer cells that can be transmitted, which concomitantly allows the host’s immune system to be more efficient in eliminating them. Although including "parasite diversity” is generally mathematically challenging, combining recent theoretical developments in studying multistrain pathogens [56] with the Red Queen models would be an interesting first attempt.


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Cancer and Post-Transcriptional Control

Modifications, such as the overexpression of miRNAs, in the post-transcriptional control of a gene can result in cancer.

Learning Objectives

Explain how post-transcriptional control can result in cancer

Key Takeaways

Key Points

  • Specific cancers have altered expression of miRNAs changes in the miRNA population of particular cancers varies depending on the type of cancer.
  • Having too many miRNAs can dramatically decrease the RNA population leading to a decrease in protein expression.
  • Studies have found that some miRNAs are specifically expressed only in cancer cells.

Key Terms

  • microRNA: a single-stranded, non-coding form of RNA, having only about 20-30 nucleotides, that has a number of functions including the regulation of gene expression
  • exosome: a vesicle responsible for the selective removal of plasma membrane proteins

Cancer and Post-transcriptional Control

Post-transcriptional regulation is the control of gene expression at the RNA level therefore, between the transcription and the translation of the gene. After being produced, the stability and distribution of the different transcripts is regulated (post-transcriptional regulation) by means of RNA-binding proteins (RBP) that control the various steps and rates of the transcripts: events such as alternative splicing, nuclear degradation (exosome), processing, nuclear export (three alternative pathways), sequestration in DCP2-bodies for storage or degradation, and, ultimately, translation.

Changes in the post-transcriptional control of a gene can result in cancer. Recently, several groups of researchers have shown that specific cancers have altered expression of microRNAs (miRNAs). miRNAs bind to the 3′ UTR or 5′ UTR of RNA molecules to degrade them. Overexpression of these miRNAs could be detrimental to normal cellular activity. An increase in many miRNAs could dramatically decrease the RNA population leading to a decrease in protein expression. Several studies have demonstrated a change in the miRNA population in specific cancer types. It appears that the subset of miRNAs expressed in breast cancer cells is quite different from the subset expressed in lung cancer cells or even from normal breast cells. This suggests that alterations in miRNA activity can contribute to the growth of breast cancer cells. These types of studies also suggest that if some miRNAs are specifically expressed only in cancer cells, they could be potential drug targets. It would, therefore, be conceivable that new drugs that turn off miRNA expression in cancer could be an effective method to treat cancer.

MicroRNA: Overexpression of miRNAs could be detrimental to normal cellular activity because miRNAs bind to the 3′ UTR of RNA molecules to degrade them. Specific types of miRNAs are only found in cancer cells.

Tumor Cell Population Dynamics

In order to describe the population dynamics of evolving tumors, different modeling approaches have been used. Population genetics models, based on the Wright–Fisher process or the Moran process, can be used to model the fate of individual cells in a population [53]. More generally, branching processes have frequently been employed to account for stochastic fluctuations in the growth and composition of the population (Fig 1) [54,55]. These stochastic models or their deterministic approximations can often be solved analytically under simplifying assumptions, which allows for computing key quantities of interest, including the probability of and time to fixation of a mutant and the size and age of the tumor cell population. By contrast, models with more intricate features, such as population structure or cellular interactions, quickly become intractable. Cellular automata are a popular choice for this model class, whose analysis relies on forward simulations [56]. Thus, simple models can provide easy-to-capture insights at the risk of oversimplification, while complex models may capture more details of the evolutionary process at the cost of being difficult to analyze comprehensively.

Population genetics modeling of cancer has addressed many aspects of this somatic evolutionary process, including tumor initiation, tumor progression, and drug resistance development. Tumor initiation models aim at identifying the rate-limiting steps in the first transformations of a normal cell. Early in cancer research, a dichotomy was identified between (1) oncogenes that, when gaining increased activity through mutations, directly promote cancer (by enhancing the ability of the cell to grow and proliferate, for example) and (2) tumor suppressor genes that normally protect against cancer (by initiating programmed cell death upon signs of uncontrolled growth, for example). Tumor initiation models have highlighted the different dynamics of oncogene activation versus tumor suppressor gene inactivation, the role of chromosomal instability, and the importance of the spatial structure of the tissue of origin [57].

Tumor progression models focus on the process of mutation accumulation and further neoplastic transformation in an initiated tumor. These models have been used to infer the velocity at which mutant waves sweep through the cancer cell population and to elucidate how this speed of adaptation depends on the mutation rate, the fitness advantage of driver mutations, and on the feasible set of mutational pathways [58–60]. The tumor progression dynamics can also inform the discrimination of driver from passenger mutations [61,62], as driver mutations are commonly predicted by detecting genes under positive selective pressure. Evolutionary models can quantify the probability of any mutation to reach fixation in a tumor cell population, including advantageous drivers as well as neutral or even deleterious passengers hitchhiking on advantageous clones [63].

Mathematical models of drug resistance development date back to Luria and Delbrück [64], who studied viral resistance in bacteria, and Goldie and Coldman [65], who analyzed drug resistant tumor subclones. The key conclusion of these and other studies is that drug resistance mutations are much more likely to preexist in the tumor prior to treatment, as opposed to being generated under treatment. The probability of a preexisting single-gene mutation is generally high, such that resistance against any drug targeting a single gene can be expected to be implanted in any large tumor [66,67]. These predictions have been confirmed repeatedly. For example, in colorectal carcinomas, resistance to epidermal growth factor receptor (EGFR) inhibitors has recently been observed after a fairly constant time period, supporting the notion that resistance is a fait accompli [12]. These dynamics of evolutionary escape from selective drug pressure suggest that long-term tumor suppression can only be achieved by therapies targeting more than one pathway. Indeed, using branching processes, it has been predicted that combination therapies have a considerably higher probability of success than sequential monotherapies of the same drugs [68].

Mathematical modeling of tumor cell population dynamics will result in models and software tools that are potentially predictive of disease progression and treatment outcome. At present, much of the large-scale sequencing that has taken place is of limited depth and geographical scope, and mathematical models based on such information will likely be crude and approximate. To construct realistic models of the evolutionary processes taking place, we need to combine models that are representative of the processes taking place with high-resolution data. In the long run, ecological models of the entire tumor microenvironment may play this role [69]. The best current candidate for an approach is single-cell sequencing. By utilizing such data, in both spatial and temporal capacities, along with information obtained in parallel experiments, such as ultra-deep sequencing of circulating tumor DNA, exosomes, or cells, an accurate picture of tumor heterogeneity and evolution dynamics will potentially be realized. To achieve this with decent precision will likely require information from thousands of individual cells. Furthermore, to gain an appreciation of the variation of these processes across different tumors will require such data from patient numbers similar to the recent ICGC and TCGA consortia. Although these requirements are beyond current capabilities, continuing improvements in current technologies and the introduction of new methods such as nanopore sequencing are likely to see a climb in data resolution and will result in a need for such mathematical approaches.

Cancer cryotherapy: evolution and biology

Since the inception of cryosurgery in the 1850s, landmark advances in chemistry, physics, materials science, and biology have culminated in the sophisticated cryosurgical devices currently in use. Effective cryosurgical tissue injury depends on four criteria: 1) excellent monitoring of the process 2) fast cooling to a lethal temperature 3) slow thawing and 4) repetition of the freeze-thaw cycle. Meeting these criteria depends on understanding the imaging technology used to visualize the iceball, the type of cryogen used, the size of the probe, and probe arrangement. Third-generation cryosurgical equipment offers advantages over previous designs. These machines rely on argon for freezing but also use helium to warm probes and accelerate the treatment process, and they offer additional safety by being able to rapidly arrest iceball formation. Metallurgic advances have led to the development of thinner probes, which have been easily adapted to perineal templates similar to those used for prostate brachytherapy.


Diagrammatic representation of the application…

Diagrammatic representation of the application of the Joule-Thomson effect for both freezing and…

(A) Graphic representation of iceball…

(A) Graphic representation of iceball temperature as a function of time after initiation…

Cryotherapy with 17-gauge cryoprobes is…

Cryotherapy with 17-gauge cryoprobes is similar to that of brachytherapy (radioactive seed implantation).…

Direct cell injury from freezing.…

Direct cell injury from freezing. As the temperature falls to below 0°C, water…

Temperature profiles generated in a…

Temperature profiles generated in a gelatin phantom with 3-mm and 1.5-mm (17G) cryoprobes…

The Ecology and Evolution of Cancer: The Ultra-Microevolutionary Process

Although tumorigenesis has been accepted as an evolutionary process (20, 102), many forces may operate differently in cancers than in organisms, as they evolve at vastly different time scales. Among such forces, natural selection, here defined as differential cellular proliferation among distinct somatic cell genotypes, is particularly interesting because its action might be thwarted in multicellular organisms (20, 29). In this review, selection is analyzed in two stages of cancer evolution: Stage I is the evolution between tumors and normal tissues, and Stage II is the evolution within tumors. The Cancer Genome Atlas (TCGA) data show a low degree of convergent evolution in Stage I, where genetic changes are not extensively shared among cases. An equally important, albeit much less highlighted, discovery using TCGA data is that there is almost no net selection in cancer evolution. Both positive and negative selection are evident but they neatly cancel each other out, rendering total selection ineffective in the absence of recombination. The efficacy of selection is even lower in Stage II, where neutral (non-Darwinian) evolution is increasingly supported by high-density sampling studies (81, 123). Because natural selection is not a strong deterministic force, cancers usually evolve divergently even in similar tissue environments.


  1. Mam

    Which gracefully topic

  2. Segenam

    Bright !!!!!

  3. Jakome

    The post was ordered by our government :)

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