Cancer Across the Tree of Life
Cancer Across the Tree of Life
Cancer is ubiquitous across the tree of life in multicellular organisms which includes animals, plants, and fungi. This is because multicellular organisms are composed of complex cellular societies that require intricate coordination and cooperation in order to sustain their host organism. Cancer occurs when this coordination breaks down, and a lineage of proliferating cells ceases cooperation with the rest of the body by ignoring signals to stop dividing and to cheat programmed death. Since cells are independent biological entities that are subject to the mechanisms of evolution in the same way organisms are, understanding the evolution of cancer requires an analysis at two levels of biological organization: the cell and the organism. At the organismal level, the natural selection of various features such as body size, reproductive traits, and ability to repair tissues can explain susceptibility to cancer. However, the same processes can also explain the evolution of specialized mechanisms that help resist cancer. At the cellular level, features within the cellular microenvironment influence the somatic evolution of cancer cells in the same way that macro environments shape organismal evolution.
This case examines the universal features of cancer across the multicellular tree of life and explores the evolutionary mechanisms that shape cancer risk within mammals at both the organismal and cellular level.
Trade-offs
- Explain how DNA influences the expression of phenotypes and describe the series of biological processes that occur. Define the concept of gene variants
- Define mutation and explain the difference between somatic and germline mutations. Describe how mutations may lead to the development of cancer
- Describe the difference between proto-onco genes and tumor suppressor genes, and explain how variants of these genes may increase risk of cancer
Cancer and trade-offs
An evolutionary trade-off refers to a situation in which evolution cannot optimize the fitness associated with a specific trait without compromising the fitness associated with another. Many aspects of a multi-cellular organism’s fitness relies on cell movement and proliferation (e.g. the ability to grow and repair tissue). Since these processes require cell proliferation, they can be limited by cancer suppressing mechanisms that have evolved to restrict proliferation. Therefore, organisms need to balance the benefits associated with the ability to grow and repair tissue with the cost of being more vulnerable to cancer (i.e. a trade-off!). The management of this trade-off can be viewed as a “balancing act” that organisms must carefully manage. If too much pressure is put on one side, the organism is at risk of being unable to successfully grow, heal, and reproduce. Too much pressure on the other, and the risk of cancer can become high. In other words, the natural selection of mechanisms that support processes such as would healing, reproduction, and growth contribute to explain why organisms such as animals remain susceptible to cancer.
Wound healing and cancer
- 1) Hemostasis
- 2) Inflammation
- 3) Proliferation
- 4) Tissue remodeling
- Without proliferation, tumors cannot grow, and tissue cannot repair
- Sustaining proliferative signaling: In cancer, proliferation is uncontrolled and disorganized, whereas wound healing triggers a coordinated proliferative response
- Activation of invasion: Cancers become deadly when they become invasive to other parts of the body
- Wound healing requires this process for cells to migrate over the wound provisional matrix
- Inflammation:
- Cancers are often a consequence of long-term, chronic inflammation
- In wound healing, inflammation works to prevent microbial colonization at the wound
- Angiogenesis:
- Tumors cannot grow beyond 1mm without their own vascular supply
- Similarly, wound healing results in the formation of new blood vessels
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- Mechanisms that help organisms resist cancer may also result in costs associated with wound healing (i.e. think back to the balancing act metaphor)
- Similar to body growth, we need to take a life-history approach to understand the relationship between wound healing and cancer risk within individual species
- With life history theory, we can make the following predictions about trade-offs in cancer resistance and wound healing:
1)Organisms that are more likely to experience tissue damage are also more likely to have a reduced ability to suppress tumors
2)Organisms that have a “fast” life history strategy benefit more from improved tissue repair ability, even with the increased cancer risk
Future studies should attempt to empirically test these predictions by comparing the relationship between tissue repair ability and cancer resistance across the tree of life
Reproduction at the cost of health
Ultimately, the reproductive success of an organism is what determines the degree to which their alleles are represented in the next
generation. Sometimes, traits that result in higher reproductive success yield consequences for an individual’s overall health.
Reproductive trade-offs and body size
For example, natural and sexual selection favor larger body sizes in many contexts, and this increase in body size may result in an increased susceptibility to cancer. These mechanisms may in part explain the persistence of high cancer risks within species over evolutionary time. Conversely, the association between body size cancer risk has been hypothesized as a factor that has limited the evolution of large body sizes across species, and explains some of the variation seen in body size within species
Reproductive trade-offs and sexual ornaments
Body size and Peto’s paradox
If multicellular growth increases the risk of cancer, then one would predict that larger organisms would have higher rates of developing tumors. Within species, this tends to remain true: larger individuals tend to have an increased risk of developing tumors. However, this is not what we observe when looking across species, where there appears to be no strong trend between average body size and cancer risk. In fact, large animals seem to be at a slightly lower risk. This inconsistent trend between and within is called Peto’s paradox.
Trade-offs and Peto’s paradox
Life History and Mechanisms of Cancer Resistance
- Explain how DNA influences the expression of phenotypes and describe the series of biological processes that occur. Define the concept of gene variants
- Define mutation and explain the difference between somatic and germline mutations. Describe how mutations may lead to the development of cancer
- Describe the difference between proto-onco genes and tumor suppressor genes, and explain how variants of these genes may increase risk of cancer
Elephants and TP53
- African Elephants and their close relatives have ~20 extra copies of TP53, a gene that plays a role in tumor suppression
- TP53 suppresses tumors by influencing apoptosis (controlled cell death)
- When an elephant cell has damaged DNA, it is more likely to undergo apoptosis compared to cells from species with less copies of TP53 (including humans)
Naked Mole Rats and hyaluronan
Naked mole rats are small subterranean mammals that are especially long-lived compared to other rodents their size (~15 years in the wild, compared to the 1-2 year lifespan of the common rat). They are the only mammal species with a eusocial mating system. In this eusocial system, individuals live in colonies where only one female (the queen) and 1-3 males (breeders) reproduce. Since becoming reproductive requires social “ascendency”, individuals are typically not reproductive until an old age, compared to other rodents.
- Naked mole rats excrete high-molecular-mass hyaluronan (HA)
- When HA is removed by knocking down the HAS2 gene, naked mole rat cells placed in mice hosts become susceptible to malignant tumor formation
It is hypothesized that HA evolved in the species to enhance skin elasticity required for navigating tight underground tunnels, and was then co-opted into cancer resistance suited for the species’ slow life history strategy
Bats and
Similar to naked mole rats, bats are small mammals that also tend to live to a long age (some species live up to 30 years!) compared to other size-matched relatives. Most species of bats only produce a single offspring per year, which is also atypical for mammals of this size. Across species, a decreased rate of DNAm predicts increased longevity. Cross-species analyses suggest that bats have relatively low DNAm rates, which may help explain their exceptional longevity. There also appears to be overlaps in genes associated with immunity, longevity, and tumor development. This suggests that low DNAm rates may be a mechanism to help protect bats from cancer
Telomeres and cancer resistance
Somatic Evolution
Tumor heterogeneity
Cancer stem cells
- The cancer stem cell (CSC) theory is supported by the knowledge of the general behavior of stem cells.
- Stem cells are self-renewing and will give rise to post-mitotic, fully differentiated, cells. They, themselves, remain undifferentiated. This behavior occurs in some tumor cells.
- In a growing tumor, small numbers of cancer stem cells seem to be responsible for generating the majority of its mass.
- Individual CSCs thus can give rise to clones of cells that share morphologies and behavior. CSCs are also called tumor initiating cells.
Ecology
The ecology of cancer cells
The ecology of a population defines the major factors that influence the natural selection of organisms, and an organism’s fitness is characterized by its success in its current environment. In the same way that organisms live in communities with other species, cooperate and compete for resources, avoid predation and dangers, and seek reproductive opportunities, somatic cells live in microenvironments with distinct ecological properties. Therefore, understanding the somatic evolution of cancer lineages also requires an understanding of the ecological principles that shape the microenvironment of cells 
Cancer and cooperation
One way cooperation can occur in nature is when neighboring individuals share common genes (i.e. are related). Generally, the more related two individuals are, the more an individual is expected to contribute to cooperation. Specifically, cooperative behavior can be favored by natural selection when the cost of an action is less than the product of the relatedness and benefit of the action. This is called Hamilton’s Rule. Since somatic cells are comprised of clonal lineages, cooperation with other clones is always advantageous. When somatic mutations occur that lead to lineages of cancerous cells, these cells are still highly related to non-malignant neighboring cells. Thus, cancer cells can receive fitness-enhancing factors such as growth signals from these healthy cells. Furthermore, cells within cancer lineages may evolve to cooperate with each other – If a mutation that promotes cooperation between cancer cells arises, it will be selected for in the lineage.
Cancer and resource acquisition
All living things require consistent access to resources for growth, survival, and reproduction. Acquiring these resources is one of the greatest challenges organisms face in terms of time and energy spent. Access to resources depends greatly on the environment that the organism inhabits. Cancer cells require a lot of energy due to their rapid rate of replication, and thus require a lot of resources. Lineages of cancer cells have a tendency to rapidly evolve strategies to exploit access to as many cellular resources as possible within their microenvironment. It has also been hypothesized that tumors are more likely to emerge when the amount of resources in the cellular microenvironment are high. This is a possible mechanism to explain the link between obesity and cancer risk.
Eco-evolutionary feedback loops
Eco-evolutionary feedback loops occur when populations evolve in response to ecological conditions, and these evolved populations express different phenotypes that influence the ecological factors of the environments they inhabit. These altered ecological features may then act as a new selective pressure on the population, and thus “feedback” to influence the evolutionary trajectory of the population. In the case of cancer, tumors tend to rapidly deplete their local microenvironments of the resources required for growth. Although this means that the cancer cells have altered their ecology in a way that is disadvantageous, new variants may arise that allow for novel strategies such as signaling for angiogenesis (the creation of new blood vessels) in order to deliver new resources to the tumor. Under these ecological conditions, these variants will rapidly be selected for, resulting in a population of cells that can effectively initiate angiogenesis. Another possible strategy that may evolve under these resource depleted conditions is metastasis (moving to other parts of the body). By moving to other parts of the body, the cancer cells can gain access to more cellular resources required for growth and replication.
Predation by immune cells
A predator-prey “arms race” is a coevolutionary process, meaning that the evolution of one species influences the evolution of another. When predators use specialized tactics to capture and kill their prey, the prey population will often evolve some sort of defense or resistance to this tactic. Once the prey resistance tactic becomes more prevalent in the population, the predator population often evolves a more elaborate tactic to counter the resistance. This is considered an “arms race” as the evolution of one species is theoretically expected to continuously feedback to affect the evolution of the other. Similar to predator and prey interactions in macro-environments, cancer and immune cells are in a constant evolutionary arms race. Immune cells are designed to kill other somatic cells that are a potential threat to become cancerous, such as cells with damaged DNA. Cancer cells have been shown to evolve strategies such as the ability to mimic the signals sent by healthy cells in order to evade immune cells, and immune cells then “adapt” their mechanisms to deal with these cheating cancer cells.
Phenotypic plasticity
Phenotypic plasticity is when a single genotype is capable of expressing multiple distinct phenotypes depending on the environment they are present in. Plasticity typically represents an adaptation by allowing an organism to maximize its fitness across multiple environmental contexts. Since cancerous lineages are comprised largely of clones (or very genetically similar cells), phenotypic plasticity is highly advantageous and helps cancer lineages to initiate, progress, and even resist treatment. The processes of evolution allow for changes in the average phenotype expression in cancer lineages across different microenvironments over time, but phenotypic plasticity can allow cancer cells to adjust to changes in their microenvironment in real-time. For example, cancer cells have been shown to switch between being specialized for either proliferation within the tumor, or invasion to new tissues.
