Evolution and cancer follow like a shadow, and evolution shapes life and creates cancer. On the tree of life, from sponges to cactus, from dogs to elephants, scientists have discovered the remains of evolution in them - cancer.

Evolution follows cancer, and evolution has shaped life and created cancer. On the tree of life, from sponges to cactus, from dogs to elephants, scientists have discovered the remains of evolution in them - cancer. But at the same time, we have also discovered new mechanisms to inhibit tumors.

This article is authorized to be excerpted from "Crazy Cells: The Evolutionary Story of Cancer and the Way of Healing" (CITIC Publishing House ) Chapter 4 "Cancer Tree of Life", the title is added by the editor, and the content has been deleted and modified.

Written by Athena Aktipis (Associate Professor, Arizona State University)

Translation by Li Zhaodong

When Joshua Schiffman (Joshua Schiffman) Bernz mountain dog was diagnosed with cancer, Schiffman couldn't believe it was true. Schiffman is a cancer scientist and a pediatric oncologist, and himself a cancer survivor. What he never expected was that his beloved pet also became a victim of the disease he studied, which he had suffered when he was a teenager. Schiffman realized that cancer is not just a disease that affects humans, it also affects many other creatures on the Tree of Life.

His own pet has cancer. This experience prompted Schiffman to learn more about dogs’ susceptibility to cancer. He was surprised to find that it has many similarities with human cancer susceptibility. Like humans, mutations in the BRCA1/2 gene can also increase the risk of breast cancer and ovarian cancer in dogs. Cancer cells in dogs also have TP53 mutations. In humans, mutations in TP53 genes can lead to a syndrome called Lee-Fomeni. This is a hereditary disease, and patients are more likely to develop cancer throughout their lives. Dogs with chronic myeloid leukemia were even found to carry BCR/ABL chromosomal translocations, which are the same as the chromosomal translocations I discussed in Chapter 3, and are very typical in human chronic myeloid leukemia. [1]

The similarity between cancer in dogs and human cancers is far more than just genetic risk factors, such as changes in BRCA, TP53 and BCR/ABL genes. Both dogs and humans have cancer risks associated with larger body sizes. [2] In the previous chapter, we saw that because of the trade-off between cell proliferation of and controlling cell behavior, the rapid growth of the body will lead to higher cancer risks. When biological individuals walk on the developing balanced steel cable, their cells must balance between excessive proliferation and excessive control so that individuals can develop normally and become evolutionary fittests after adulthood. So if all other factors are the same, we may see larger organisms more susceptible to cancer.

However, other factors are not all the same - at least the elephant is a counterexample. Elephants have 100 times more cells than us, but their cancer incidence is much lower than ours. [3] In fact, if we compare different species, we will find that larger sizes do not pose a higher risk of cancer, and the correlation between this higher cancer risk and larger size seems to occur only within the species. In the previous chapter we knew that getting bigger size increases cancer risk because more cells are needed to divide to grow into a larger body and maintain it. So, why is there no correlation between body size and cancer risk among species?

In this chapter, I will tell you how evolution solves this problem called the Petto paradox [4]. I will also carefully explore some of the reasons why different species on the Tree of Life differ in susceptibility to cancer, from the simplest multicellular organism to large, complex organisms such as elephants.Understanding how cancer affects other life forms and how life evolves its ability to suppress cancer can help us gain insight into why we, as humans, are susceptible to cancer and provide guidance on developing new cancer treatment and prevention strategies.

cancer is spread all over different life forms

At the beginning of this book, I talked about cactus and their breathtaking coronal, jointed and growth structures like the brain that they produce due to the loss of control of normal cell proliferation. These cactus are curious because essentially, they are the cactus versions of cancer—cells have successfully escaped the normal limits of multicellular behavior and began to grow out of control.

Crested cactus is an example of a decorative plant. Plants like cactus are actually diverse in shape, and their growth patterns often have many different surfaces (faces) . Therefore, scholars use the term "adhesive" (fasciation) to describe it. Affixation may occur when the cell at the tip of the plant (called meristem cell ) expands from a single tip into a row of cells. When these cells divide, they form an enlarged proliferating cell belt, which grow into fan shapes and sometimes even fold up to form a growth pattern like the human brain. This affixation phenomenon is not limited to cactus, it also occurs in many other plants. Some flowers can be decorated and grow into strangely shaped and elongated flowers. Tobacco plants also often undergo detoxification, changing the shape of their leaves and the pattern of their flowering. Even large trees like pine trees may become decalized, causing the trunk to become wide and heavy, and look unstable. As they grow taller, these trunks expand into the shape of a fan.

The crowned coarse branched casuarina did not grow a typical branch structure, but instead formed a large fan shape composed of tissues with dysfunctional differentiation.丨Photo source: Forest and Kim Starr/Flickr

For many years, my interest in cactus made me fascinated by the phenomenon of arranging, and later further expanded to the entire tree of life, eventually covering all branches of multicellular life. From a technical perspective, green algae also belongs to plants - all organisms including tall pine trees to scum in ponds. My colleagues and I found that cancer and cancer-like life phenomena occur in green algae, and among all other branches of the Tree of Life. We have found evidence of their existence in clams, insects, various animals, corals, , fungi, and of course plants.

We found reports of cancer and cancer-like phenomena (dysregulation of differentiation and hyperproliferation) on every branch of multicellular life.丨Photo source: References [5]

We also found that among all these different species, the occurrence of cancer is always related to violating the basic principles of multicellular cooperation: the destruction of cell proliferation regulation, abnormal cell survival, chaotic cell division of labor (in other words, cell differentiation process is out of control) , the monopoly of nutrient resources and the destruction of the extracellular environment. As I mentioned earlier, cancers and cancer-like phenomena in different species can be discussed using the common framework of cell cheating. Unlike many other definitions we can use, defining cancer as cell cheating can allow us to discuss cancer across biologically different species.

Generally speaking, cancer is an animal-centric definition, using cancer cell invasion and metastasis as standards. Cell invasion requires cells to break through their base membrane, but not all organisms are wrapped in the base membrane, and not all organisms have circulatory systems that facilitate cancer cell metastasis. To define cancer, focusing on cell cheating would be a more general approach, allowing us to use a broad set of features that are closely related to various parts of multicellular collaboration.

Many biologists believe that aggressive cancer cannot occur in plants because plants have cell wall and a more fixed tissue structure. However, we have seen that plants are susceptible to the growth of (adhesed) . Although these growths are not aggressive, they have all the characteristics of cancer-related cell cheating: excessive cell proliferation, no death of cells that should die, monopoly of nutrient resources, collapse of cell division of labor system (the shape of the flower is destroyed) , and destruction of the shared environment between cells (for example, increasing the likelihood of tissue death, making the whole plant more susceptible to infection) . Moreover, aggressive growth can sometimes occur in plants. When we reviewed the cancer on the Tree of Life, we were surprised to find that a paper reported an aggressive growth in plants—the researchers found a row of aggressive cells that broke through existing tissues [6].

This aggressive growth can even meet the stricter traditional definition of cancer, which suggests that plants may also get cancer based on all detection methods and definition criteria.

So far, we have not found any animal that is completely cancer-free in database (a database of comprehensive cancer records created by Amy Boddy of the University of California, Santa Barbara, , about 170,000 animal records from about 13,000 species )—at least one tumor case exists in each species with at least 50 animal records. At the time of writing, the species with the highest incidence of cancer found in the database were ferret , hedgehog and guinea pig . Other animals with very high cancer incidence include cheetahs and Tasmanian devils (even in cases where cases of contagious facial tumors that Tasmanian devils are still very high) .

In addition to building a cross-species cancer risk database, we are also studying flat disc animals and sponges - we found that looking at the cancer situations of all species, these "simple" life forms seem to be able to resist cancer (the flat disc animals and sponges are not in the comparative oncology database we discussed above, because they are not usually treated by veterinarians or in zoos, and the data in the database are obtained from both) .

My colleague and collaborator Angelo Fortunato (Angelo Fortunato) is responsible for the project, focusing on these ancient multicellular life forms and studying their ability to fight cancer.

Fortunato focused on several species that seem to not get cancer (no reports of cancer in our initial literature review were found in our initial literature review) . The first species he studied in the lab included a sponge, called Tethya wilhema, a creature that was almost just a collection of basically undifferentiated cells with small holes and channels in the body where water and nutrients can flow through them. Fortunato found that sponges can be said to have extremely strong anti-cancer ability; they can tolerate extremely high radiation (which induces DNA damage) without any obvious carcinoid growth. He noticed that while observing the sponges' response to radiation, sometimes they shrink for a few days and then bounce to their previous sizes without the obvious strange growth or color changes he could observe to indicate the onset of the cancer. Fortunato is currently using molecular biology technology to try to reveal the mechanisms that lead to this seemingly adaptive ability to resist DNA damage.

He is also studying the anti-cancer ability of silk worm (Trichoplax adhaerens, a flat disc animal). This organism is theoretically an animal, but in fact it is basically a bag of cells, and there is a layer of skin composed of cells to help it move. When Fortunato placed the silk worms under radiation, he sometimes observed some dark areas of (probably cancer cells) growing inside them.Sometimes these darkened areas move to the outer edge of the organism, then appear to be squeezed or pinched away, and the dark cells no longer exist.

This may be a cancer suppression mechanism, and organisms like scattered animals that do not have complex tissues and organ systems use this mechanism to remove potential problem cells. This strategy seems to work only in simple organisms, but if you continue to delve into it, squeeze out and pinch the cells, it may also seem like a feasible strategy for tissue level or even large organisms like humans. For example, in human colon , excessively proliferating cells will be squeezed out by their cell neighbors. Cells in adjacent areas can produce a series of actosin (the component of muscle) , forming a circular shape, and forcefully extruding these problematic cells. [7]

Fortunato's research has given us a little understanding of the ways simple organisms evolved to protect themselves from cell cheating. At the same time, it also encourages us to ask questions and expand our reference system - examine the entire tree of life to better understand how our cancer suppression mechanism evolved.

more cells, more cancers?

In the previous section, I discussed the mechanism of cancer suppression in small and simple life forms, but what happens in larger and more complex organisms (such as humans and elephants) ? How can large and complex organisms control cancer for a long enough time and eventually reproduce successfully?

To become a multicellular organism, cell proliferation is essential, but it will also increase our susceptibility to cancer, because mutations can appear in dividing and proliferating cells at any time. The larger the organism, the more cell divisions are required to grow into a body size of this size, and the more cell divisions are required to maintain the body size (because the tissue needs to be constantly updated) . In addition, the larger the organism, the more cells that may mutate at any time. In fact, if we look at the incidence of cancer within a species, we will find that larger individuals are at a higher risk of cancer. For example, large canine (weight more than about 20 kg) has a higher risk of cancer than smaller canines [8]. Similarly, tall people in humans have a higher risk of cancer than shorter people. For every 10 cm of height, the risk of cancer increases by about 10% [9]. However, if compares different species horizontally, this pattern of larger size and greater cancer risk will no longer hold [10].

At the beginning of this chapter, we talked about the number of elephants' cells as many as 100 times that of humans, but their risk of developing cancer is not 100 times that of us. With the size and lifespan of elephants, their resistance to cancer is surprising. In fact, elephants have much lower cancer rates than many smaller animals, including humans. On the other hand, mice are more likely to get cancer than us, although they are much smaller than ours. This paradox also exists in lifespan: the longer the lifespan, the longer the cell divides and is exposed to potentially induced mutations, and the corresponding cancer has more chances. However, when we compare cancer risks among different species, we find that there is no correlation between cancer incidence and lifespan in each species.

cancer risk is not related to body size and lifespan. This phenomenon is called the Petto paradox, proposed by Sir Richard Petto, a statistical epidemiologist at the University of Oxford, (Sir Richard Peto) in the 1970s. He pointed out that from the cellular level, human cells must have stronger anti-cancer ability than mouse cells, otherwise we will die of cancer [11].My colleagues and I have confirmed this phenomenon in the past few years: species with longer lifespans and larger sizes are not higher than those with shorter lifespans and smaller sizes.

Decision-making in life history

In the journey of life, we all walk on the tightrope, balancing the freedom and control of cells. Giving too much freedom to cells will increase our risk of cancer, while too much control over cells will put us at the risk of growth stagnation and evolution failure. The same is true for other multicellular organisms.

Elephants play long-term games: they have children later and have no natural enemies, so they invest more in cancer suppression to allow themselves to live long enough to get the rewards of the strategy. This means they have to walk through a longer steel cable to reach the point where they get reproductive rewards. Not only do they have to tilt a little to the right a little so that they are more likely to eventually get this reproductive reward, but they must also achieve better balance overall if they are to live to the age of successful reproduction.

The tilt of the organism towards a greater cell freedom, more confusing, and higher cancer risk is part of the force that comes from the inside of the organism, and the other part comes from the outside of the organism, such as DNA damage caused by solar radiation or chemical mutagenic substances. As biological populations evolve over generations, other factors can also affect this balance between cell freedom and control, such as the high mortality rate of external causes (the possibility of death due to external reasons such as hunting by natural enemies) and strong sexual choice (the success of reproduction is strongly affected by the ability to attract the opposite sex and compete with the same sex) . These evolutionary pressures actually choose organisms that adopt the "left" strategy, because if you don't live long enough (or if you have to give up a lot of reproductive opportunities in exchange for a lower risk of cancer), the benefits of suppressing cancer become trivial compared to the price you have to pay for it.

In evolutionary biology, these trade-offs are called trade-offs in life history because they affect the strategies of organisms to invest in various "targets" (such as growth, reproduction, and survival) throughout their lives. The basic concept of life history theory is that the resources used by organisms to achieve various goals to ultimately improve their reproductive success rate (such as time and energy) are limited. Invest more resources in one thing, and the resources left for another thing must be reduced.

We have seen that effective cancer suppression strategies often come at a cost. Too strong ability to inhibit cancer will affect other characteristics related to adaptability. This is one of the reasons why organisms have evolved with cancer for hundreds of millions of years and have not been able to completely suppress cancer. We have also seen that excessive inhibition of cancer can have a negative impact on life.

Artificial choice in agriculture provides a unique window for us to understand these trade-offs between characteristics related to evolutionary adaptation and cancer risk. We will selectively breed animals to get certain traits, such as egg laying and milking. This strict manual selection can sometimes produce unexpected results, helping us understand the tradeoffs behind certain traits. An example is a hen that is specially cultivated for laying eggs. In addition to laying more eggs, their ovarian cancer incidence is also higher, probably because after selection, their ovaries and their surrounding tissues are more tolerant of cell proliferation [13].

The seasonal rapid growth of deer antlers also shows that cancer suppression is a delicate balance. In winter, deer grinds away the antlers, and then the antlers grow rapidly in spring and summer to prepare for the autumn breeding season [14]. These bucks antlers are also more likely to grow a strange cancer-like thing called antler tumor. To grow extremely quickly, these antlers not only require rapid proliferation of cells, but also strictly control them to prevent the growth of the antlers from being completely out of control.There are many signs that there is an association between cancer-related signaling pathways and the ability of antlers to grow rapidly. Even for normal antlers without deer antler tumors, their gene expression pattern is more like bone cancer (rather than normal bone tissue ) [15].

In addition, tumor-promoting genes will also be expressed in such deer antlers. Gene sequencing results show that the cancer-related gene (protooncogene) has always been positively selected among deer ancestors [16]. These antlers indicate that sexually selected traits (because females are more likely to mate with males with larger antlers) may increase cancer susceptibility [17].

To become a huge organism, it requires stronger cell proliferation ability - this is a prerequisite for them to grow to such a large body and maintain their size, which also means they are at a higher risk of cancer. But when we compare different species, this relationship doesn’t exist. Elephants and other slow-living creatures have gained some tricks during their evolution, allowing them to have both huge sizes and fight cancer.

Elephants have many additional copies of the tumor suppressor gene TP53, making their cancer incidence very low. (While we humans only have two copies of TP53, one from the mother and the other from the father.) As mentioned earlier, TP53 helps control cell proliferation, and when the cell is damaged too much to repair, it will induce programmed cell death. TP53 is like a cheat detector for the genome, monitoring the abnormal behavior of cells and responding accordingly. TP53 is just one of many tumor suppressor genes, but it is the most important one: it can help cells maintain healthy state by monitoring abnormalities such as DNA damage. If it detects damage, it stops cell division cycle until the problem is solved. If the problem cannot be solved, TP53 will initiate the cell suicide program, and enable a series of signals to transduce , which will eventually lead to cell apoptosis. These cancer suppression functions of elephants are also particularly powerful due to the additional presence of TP53 copies: they are particularly sensitive to DNA damage, so when the damage occurs, their cells are more likely to initiate self-destruct procedures. Research and analysis showed that elephants have 40 copies of TP53 gene, and elephant cells can easily self-destruct under radiation exposure [18].

Elephants are not the only organisms that evolved a cancer suppression system to make them bigger. Evolutionary biologist Mark Tollis (Marc Tollis, also a member of our research group) found duplications of apoptotic genes in the genome of humpback whale . Compared with the smaller cetacean (including sperm whale , bottlenose dolphin and killer whales , during their evolution, humpback whales are more inclined to be responsible for cell cycle control, cell signaling and cell proliferation. The balance between

regulation and controlled

cell freedom and cell control is a dynamic process that exists throughout life. Genes like TP53 do not constantly express protein - if so, it will push us too far to the right, and it will also produce a certain cost (such as premature aging or low fertility) . Not only does elephants tend to balance more on the right side, but they are also more careful and active in maintaining balance than small animals. Large and long-lived animals need stronger cancer suppression systems and more sophisticated regulatory mechanisms to keep organisms balanced on this cable for their lifespan. This is not only a matter of expressing more gene products and improving cell control intensity, but also a matter of needing to express an appropriate amount of gene products at the right time, so as to ensure the balance of gene product expression, otherwise the biological cells will fall into chaos.

So how do organisms regulate those regulatory factors? One way is to construct the gene network (the connection between genes so that they can be affected by each other's state) , including all genes from promoting cell freedom to promoting cell control. By monitoring and affecting the expression of gene products, these networks can help organisms maintain this delicate balance for longer periods of time (as we saw earlier on the signal monitoring function of TP53) .

is mainly responsible for making the balance bias towards cell freedom (promoting cell proliferation) The genes of are the oldest genes, and they appeared as early as the period of single-cell organisms. The genes that are mainly responsible for making balance bias towards cell control evolved during the transition from single cells to multicellular cells. Many of these genes are sometimes called caregivers, which help strengthen collaboration between cells and make multicellular organisms possible. But there is another type of gene: the gene [20]. These genes are called gatekeeper genes, which help to maintain the balance of the entire system, respond dynamically to changes, and send signals to both sides of the balance to adjust as needed.

The gatekeeper gene between "single-cell" and "multi-cell" genes is the latest in terms of evolutionary time. They allow large, long-lived life forms like humans and elephants to balance the conflict between cell freedom and cell control throughout the life cycle, making them compromise with each other. These genes can help organisms dynamically manage changing forces that would otherwise make the already difficult tightrope walking even more unstable.

Evolution follows cancer, and evolution has shaped life and created cancer. On the tree of life, from sponges to cactus, from dogs to elephants, scientists have discovered the remains of evolution in them - cancer. But at the same time, we have also discovered new mechanisms to inhibit tumors.

This article is authorized to be excerpted from "Crazy Cells: The Evolutionary Story of Cancer and the Way of Healing" (CITIC Publishing House ) Chapter 4 "Cancer Tree of Life", the title is added by the editor, and the content has been deleted and modified.

Written by Athena Aktipis (Associate Professor, Arizona State University)

Translation by Li Zhaodong

When Joshua Schiffman (Joshua Schiffman) Bernz mountain dog was diagnosed with cancer, Schiffman couldn't believe it was true. Schiffman is a cancer scientist and a pediatric oncologist, and himself a cancer survivor. What he never expected was that his beloved pet also became a victim of the disease he studied, which he had suffered when he was a teenager. Schiffman realized that cancer is not just a disease that affects humans, it also affects many other creatures on the Tree of Life.

His own pet has cancer. This experience prompted Schiffman to learn more about dogs’ susceptibility to cancer. He was surprised to find that it has many similarities with human cancer susceptibility. Like humans, mutations in the BRCA1/2 gene can also increase the risk of breast cancer and ovarian cancer in dogs. Cancer cells in dogs also have TP53 mutations. In humans, mutations in TP53 genes can lead to a syndrome called Lee-Fomeni. This is a hereditary disease, and patients are more likely to develop cancer throughout their lives. Dogs with chronic myeloid leukemia were even found to carry BCR/ABL chromosomal translocations, which are the same as the chromosomal translocations I discussed in Chapter 3, and are very typical in human chronic myeloid leukemia. [1]

The similarity between cancer in dogs and human cancers is far more than just genetic risk factors, such as changes in BRCA, TP53 and BCR/ABL genes. Both dogs and humans have cancer risks associated with larger body sizes. [2] In the previous chapter, we saw that because of the trade-off between cell proliferation of and controlling cell behavior, the rapid growth of the body will lead to higher cancer risks. When biological individuals walk on the developing balanced steel cable, their cells must balance between excessive proliferation and excessive control so that individuals can develop normally and become evolutionary fittests after adulthood. So if all other factors are the same, we may see larger organisms more susceptible to cancer.

However, other factors are not all the same - at least the elephant is a counterexample. Elephants have 100 times more cells than us, but their cancer incidence is much lower than ours. [3] In fact, if we compare different species, we will find that larger sizes do not pose a higher risk of cancer, and the correlation between this higher cancer risk and larger size seems to occur only within the species. In the previous chapter we knew that getting bigger size increases cancer risk because more cells are needed to divide to grow into a larger body and maintain it. So, why is there no correlation between body size and cancer risk among species?

In this chapter, I will tell you how evolution solves this problem called the Petto paradox [4]. I will also carefully explore some of the reasons why different species on the Tree of Life differ in susceptibility to cancer, from the simplest multicellular organism to large, complex organisms such as elephants.Understanding how cancer affects other life forms and how life evolves its ability to suppress cancer can help us gain insight into why we, as humans, are susceptible to cancer and provide guidance on developing new cancer treatment and prevention strategies.

cancer is spread all over different life forms

At the beginning of this book, I talked about cactus and their breathtaking coronal, jointed and growth structures like the brain that they produce due to the loss of control of normal cell proliferation. These cactus are curious because essentially, they are the cactus versions of cancer—cells have successfully escaped the normal limits of multicellular behavior and began to grow out of control.

Crested cactus is an example of a decorative plant. Plants like cactus are actually diverse in shape, and their growth patterns often have many different surfaces (faces) . Therefore, scholars use the term "adhesive" (fasciation) to describe it. Affixation may occur when the cell at the tip of the plant (called meristem cell ) expands from a single tip into a row of cells. When these cells divide, they form an enlarged proliferating cell belt, which grow into fan shapes and sometimes even fold up to form a growth pattern like the human brain. This affixation phenomenon is not limited to cactus, it also occurs in many other plants. Some flowers can be decorated and grow into strangely shaped and elongated flowers. Tobacco plants also often undergo detoxification, changing the shape of their leaves and the pattern of their flowering. Even large trees like pine trees may become decalized, causing the trunk to become wide and heavy, and look unstable. As they grow taller, these trunks expand into the shape of a fan.

The crowned coarse branched casuarina did not grow a typical branch structure, but instead formed a large fan shape composed of tissues with dysfunctional differentiation.丨Photo source: Forest and Kim Starr/Flickr

For many years, my interest in cactus made me fascinated by the phenomenon of arranging, and later further expanded to the entire tree of life, eventually covering all branches of multicellular life. From a technical perspective, green algae also belongs to plants - all organisms including tall pine trees to scum in ponds. My colleagues and I found that cancer and cancer-like life phenomena occur in green algae, and among all other branches of the Tree of Life. We have found evidence of their existence in clams, insects, various animals, corals, , fungi, and of course plants.

We found reports of cancer and cancer-like phenomena (dysregulation of differentiation and hyperproliferation) on every branch of multicellular life.丨Photo source: References [5]

We also found that among all these different species, the occurrence of cancer is always related to violating the basic principles of multicellular cooperation: the destruction of cell proliferation regulation, abnormal cell survival, chaotic cell division of labor (in other words, cell differentiation process is out of control) , the monopoly of nutrient resources and the destruction of the extracellular environment. As I mentioned earlier, cancers and cancer-like phenomena in different species can be discussed using the common framework of cell cheating. Unlike many other definitions we can use, defining cancer as cell cheating can allow us to discuss cancer across biologically different species.

Generally speaking, cancer is an animal-centric definition, using cancer cell invasion and metastasis as standards. Cell invasion requires cells to break through their base membrane, but not all organisms are wrapped in the base membrane, and not all organisms have circulatory systems that facilitate cancer cell metastasis. To define cancer, focusing on cell cheating would be a more general approach, allowing us to use a broad set of features that are closely related to various parts of multicellular collaboration.

Many biologists believe that aggressive cancer cannot occur in plants because plants have cell wall and a more fixed tissue structure. However, we have seen that plants are susceptible to the growth of (adhesed) . Although these growths are not aggressive, they have all the characteristics of cancer-related cell cheating: excessive cell proliferation, no death of cells that should die, monopoly of nutrient resources, collapse of cell division of labor system (the shape of the flower is destroyed) , and destruction of the shared environment between cells (for example, increasing the likelihood of tissue death, making the whole plant more susceptible to infection) . Moreover, aggressive growth can sometimes occur in plants. When we reviewed the cancer on the Tree of Life, we were surprised to find that a paper reported an aggressive growth in plants—the researchers found a row of aggressive cells that broke through existing tissues [6].

This aggressive growth can even meet the stricter traditional definition of cancer, which suggests that plants may also get cancer based on all detection methods and definition criteria.

So far, we have not found any animal that is completely cancer-free in database (a database of comprehensive cancer records created by Amy Boddy of the University of California, Santa Barbara, , about 170,000 animal records from about 13,000 species )—at least one tumor case exists in each species with at least 50 animal records. At the time of writing, the species with the highest incidence of cancer found in the database were ferret , hedgehog and guinea pig . Other animals with very high cancer incidence include cheetahs and Tasmanian devils (even in cases where cases of contagious facial tumors that Tasmanian devils are still very high) .

In addition to building a cross-species cancer risk database, we are also studying flat disc animals and sponges - we found that looking at the cancer situations of all species, these "simple" life forms seem to be able to resist cancer (the flat disc animals and sponges are not in the comparative oncology database we discussed above, because they are not usually treated by veterinarians or in zoos, and the data in the database are obtained from both) .

My colleague and collaborator Angelo Fortunato (Angelo Fortunato) is responsible for the project, focusing on these ancient multicellular life forms and studying their ability to fight cancer.

Fortunato focused on several species that seem to not get cancer (no reports of cancer in our initial literature review were found in our initial literature review) . The first species he studied in the lab included a sponge, called Tethya wilhema, a creature that was almost just a collection of basically undifferentiated cells with small holes and channels in the body where water and nutrients can flow through them. Fortunato found that sponges can be said to have extremely strong anti-cancer ability; they can tolerate extremely high radiation (which induces DNA damage) without any obvious carcinoid growth. He noticed that while observing the sponges' response to radiation, sometimes they shrink for a few days and then bounce to their previous sizes without the obvious strange growth or color changes he could observe to indicate the onset of the cancer. Fortunato is currently using molecular biology technology to try to reveal the mechanisms that lead to this seemingly adaptive ability to resist DNA damage.

He is also studying the anti-cancer ability of silk worm (Trichoplax adhaerens, a flat disc animal). This organism is theoretically an animal, but in fact it is basically a bag of cells, and there is a layer of skin composed of cells to help it move. When Fortunato placed the silk worms under radiation, he sometimes observed some dark areas of (probably cancer cells) growing inside them.Sometimes these darkened areas move to the outer edge of the organism, then appear to be squeezed or pinched away, and the dark cells no longer exist.

This may be a cancer suppression mechanism, and organisms like scattered animals that do not have complex tissues and organ systems use this mechanism to remove potential problem cells. This strategy seems to work only in simple organisms, but if you continue to delve into it, squeeze out and pinch the cells, it may also seem like a feasible strategy for tissue level or even large organisms like humans. For example, in human colon , excessively proliferating cells will be squeezed out by their cell neighbors. Cells in adjacent areas can produce a series of actosin (the component of muscle) , forming a circular shape, and forcefully extruding these problematic cells. [7]

Fortunato's research has given us a little understanding of the ways simple organisms evolved to protect themselves from cell cheating. At the same time, it also encourages us to ask questions and expand our reference system - examine the entire tree of life to better understand how our cancer suppression mechanism evolved.

more cells, more cancers?

In the previous section, I discussed the mechanism of cancer suppression in small and simple life forms, but what happens in larger and more complex organisms (such as humans and elephants) ? How can large and complex organisms control cancer for a long enough time and eventually reproduce successfully?

To become a multicellular organism, cell proliferation is essential, but it will also increase our susceptibility to cancer, because mutations can appear in dividing and proliferating cells at any time. The larger the organism, the more cell divisions are required to grow into a body size of this size, and the more cell divisions are required to maintain the body size (because the tissue needs to be constantly updated) . In addition, the larger the organism, the more cells that may mutate at any time. In fact, if we look at the incidence of cancer within a species, we will find that larger individuals are at a higher risk of cancer. For example, large canine (weight more than about 20 kg) has a higher risk of cancer than smaller canines [8]. Similarly, tall people in humans have a higher risk of cancer than shorter people. For every 10 cm of height, the risk of cancer increases by about 10% [9]. However, if compares different species horizontally, this pattern of larger size and greater cancer risk will no longer hold [10].

At the beginning of this chapter, we talked about the number of elephants' cells as many as 100 times that of humans, but their risk of developing cancer is not 100 times that of us. With the size and lifespan of elephants, their resistance to cancer is surprising. In fact, elephants have much lower cancer rates than many smaller animals, including humans. On the other hand, mice are more likely to get cancer than us, although they are much smaller than ours. This paradox also exists in lifespan: the longer the lifespan, the longer the cell divides and is exposed to potentially induced mutations, and the corresponding cancer has more chances. However, when we compare cancer risks among different species, we find that there is no correlation between cancer incidence and lifespan in each species.

cancer risk is not related to body size and lifespan. This phenomenon is called the Petto paradox, proposed by Sir Richard Petto, a statistical epidemiologist at the University of Oxford, (Sir Richard Peto) in the 1970s. He pointed out that from the cellular level, human cells must have stronger anti-cancer ability than mouse cells, otherwise we will die of cancer [11].My colleagues and I have confirmed this phenomenon in the past few years: species with longer lifespans and larger sizes are not higher than those with shorter lifespans and smaller sizes.

Decision-making in life history

In the journey of life, we all walk on the tightrope, balancing the freedom and control of cells. Giving too much freedom to cells will increase our risk of cancer, while too much control over cells will put us at the risk of growth stagnation and evolution failure. The same is true for other multicellular organisms.

Elephants play long-term games: they have children later and have no natural enemies, so they invest more in cancer suppression to allow themselves to live long enough to get the rewards of the strategy. This means they have to walk through a longer steel cable to reach the point where they get reproductive rewards. Not only do they have to tilt a little to the right a little so that they are more likely to eventually get this reproductive reward, but they must also achieve better balance overall if they are to live to the age of successful reproduction.

The tilt of the organism towards a greater cell freedom, more confusing, and higher cancer risk is part of the force that comes from the inside of the organism, and the other part comes from the outside of the organism, such as DNA damage caused by solar radiation or chemical mutagenic substances. As biological populations evolve over generations, other factors can also affect this balance between cell freedom and control, such as the high mortality rate of external causes (the possibility of death due to external reasons such as hunting by natural enemies) and strong sexual choice (the success of reproduction is strongly affected by the ability to attract the opposite sex and compete with the same sex) . These evolutionary pressures actually choose organisms that adopt the "left" strategy, because if you don't live long enough (or if you have to give up a lot of reproductive opportunities in exchange for a lower risk of cancer), the benefits of suppressing cancer become trivial compared to the price you have to pay for it.

In evolutionary biology, these trade-offs are called trade-offs in life history because they affect the strategies of organisms to invest in various "targets" (such as growth, reproduction, and survival) throughout their lives. The basic concept of life history theory is that the resources used by organisms to achieve various goals to ultimately improve their reproductive success rate (such as time and energy) are limited. Invest more resources in one thing, and the resources left for another thing must be reduced.

We have seen that effective cancer suppression strategies often come at a cost. Too strong ability to inhibit cancer will affect other characteristics related to adaptability. This is one of the reasons why organisms have evolved with cancer for hundreds of millions of years and have not been able to completely suppress cancer. We have also seen that excessive inhibition of cancer can have a negative impact on life.

Artificial choice in agriculture provides a unique window for us to understand these trade-offs between characteristics related to evolutionary adaptation and cancer risk. We will selectively breed animals to get certain traits, such as egg laying and milking. This strict manual selection can sometimes produce unexpected results, helping us understand the tradeoffs behind certain traits. An example is a hen that is specially cultivated for laying eggs. In addition to laying more eggs, their ovarian cancer incidence is also higher, probably because after selection, their ovaries and their surrounding tissues are more tolerant of cell proliferation [13].

The seasonal rapid growth of deer antlers also shows that cancer suppression is a delicate balance. In winter, deer grinds away the antlers, and then the antlers grow rapidly in spring and summer to prepare for the autumn breeding season [14]. These bucks antlers are also more likely to grow a strange cancer-like thing called antler tumor. To grow extremely quickly, these antlers not only require rapid proliferation of cells, but also strictly control them to prevent the growth of the antlers from being completely out of control.There are many signs that there is an association between cancer-related signaling pathways and the ability of antlers to grow rapidly. Even for normal antlers without deer antler tumors, their gene expression pattern is more like bone cancer (rather than normal bone tissue ) [15].

In addition, tumor-promoting genes will also be expressed in such deer antlers. Gene sequencing results show that the cancer-related gene (protooncogene) has always been positively selected among deer ancestors [16]. These antlers indicate that sexually selected traits (because females are more likely to mate with males with larger antlers) may increase cancer susceptibility [17].

To become a huge organism, it requires stronger cell proliferation ability - this is a prerequisite for them to grow to such a large body and maintain their size, which also means they are at a higher risk of cancer. But when we compare different species, this relationship doesn’t exist. Elephants and other slow-living creatures have gained some tricks during their evolution, allowing them to have both huge sizes and fight cancer.

Elephants have many additional copies of the tumor suppressor gene TP53, making their cancer incidence very low. (While we humans only have two copies of TP53, one from the mother and the other from the father.) As mentioned earlier, TP53 helps control cell proliferation, and when the cell is damaged too much to repair, it will induce programmed cell death. TP53 is like a cheat detector for the genome, monitoring the abnormal behavior of cells and responding accordingly. TP53 is just one of many tumor suppressor genes, but it is the most important one: it can help cells maintain healthy state by monitoring abnormalities such as DNA damage. If it detects damage, it stops cell division cycle until the problem is solved. If the problem cannot be solved, TP53 will initiate the cell suicide program, and enable a series of signals to transduce , which will eventually lead to cell apoptosis. These cancer suppression functions of elephants are also particularly powerful due to the additional presence of TP53 copies: they are particularly sensitive to DNA damage, so when the damage occurs, their cells are more likely to initiate self-destruct procedures. Research and analysis showed that elephants have 40 copies of TP53 gene, and elephant cells can easily self-destruct under radiation exposure [18].

Elephants are not the only organisms that evolved a cancer suppression system to make them bigger. Evolutionary biologist Mark Tollis (Marc Tollis, also a member of our research group) found duplications of apoptotic genes in the genome of humpback whale . Compared with the smaller cetacean (including sperm whale , bottlenose dolphin and killer whales , during their evolution, humpback whales are more inclined to be responsible for cell cycle control, cell signaling and cell proliferation. The balance between

regulation and controlled

cell freedom and cell control is a dynamic process that exists throughout life. Genes like TP53 do not constantly express protein - if so, it will push us too far to the right, and it will also produce a certain cost (such as premature aging or low fertility) . Not only does elephants tend to balance more on the right side, but they are also more careful and active in maintaining balance than small animals. Large and long-lived animals need stronger cancer suppression systems and more sophisticated regulatory mechanisms to keep organisms balanced on this cable for their lifespan. This is not only a matter of expressing more gene products and improving cell control intensity, but also a matter of needing to express an appropriate amount of gene products at the right time, so as to ensure the balance of gene product expression, otherwise the biological cells will fall into chaos.

So how do organisms regulate those regulatory factors? One way is to construct the gene network (the connection between genes so that they can be affected by each other's state) , including all genes from promoting cell freedom to promoting cell control. By monitoring and affecting the expression of gene products, these networks can help organisms maintain this delicate balance for longer periods of time (as we saw earlier on the signal monitoring function of TP53) .

is mainly responsible for making the balance bias towards cell freedom (promoting cell proliferation) The genes of are the oldest genes, and they appeared as early as the period of single-cell organisms. The genes that are mainly responsible for making balance bias towards cell control evolved during the transition from single cells to multicellular cells. Many of these genes are sometimes called caregivers, which help strengthen collaboration between cells and make multicellular organisms possible. But there is another type of gene: the gene [20]. These genes are called gatekeeper genes, which help to maintain the balance of the entire system, respond dynamically to changes, and send signals to both sides of the balance to adjust as needed.

The gatekeeper gene between "single-cell" and "multi-cell" genes is the latest in terms of evolutionary time. They allow large, long-lived life forms like humans and elephants to balance the conflict between cell freedom and cell control throughout the life cycle, making them compromise with each other. These genes can help organisms dynamically manage changing forces that would otherwise make the already difficult tightrope walking even more unstable.

References

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[16] Wang et al., “Genetic Basis of Ruminant Headgear and Rapid Antler Regeneration.”

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