A humpback whale is among the largest animals on this planet, now or ever. It is also a gigantic society made of quadrillions of cooperating cells. Different cell types orchestrate eating, breathing, swimming, reproduction, reacting to other animals, and all the functions that are necessary for a whale to survive and thrive. If you look inside an elephant, a person or even a saguaro cactus, you will see a similarly well-functioning cellular civilization.
Multicellular creatures evolved in the first place because cells that cooperate had advantages over loners such as a single-celled bacterium. Sharing resources allowed life-forms to become larger—a benefit that helps them resist predators—because nutrients and chemical signals that cells need could be transported around the body. Dividing labor let cells specialize and build useful parts such as a stomach or legs. And teamwork gave them the ability to maintain a healthy extracellular environment so they could live longer than they otherwise would.
But cooperation is a fragile proposition. Within multicellular life, cheaters can prosper. By hogging resources, they replicate more quickly than cooperators and take over, unless there are mechanisms to enforce cooperation. Cheating cells can take advantage of the cooperative cellular society they are living in, overproliferating, monopolizing nutrients and otherwise disrupting the harmony that makes multicellular organisms viable in the first place. This cellular cheating is what we know as cancer.
Cancer cells break the rules of normal cells. They divide when they should not, do not die when they should, rob other cells of essential supplies, shirk their cellular jobs and pollute the extracellular space. While cooperating cells curb excess growth and proliferation, cancer cells often evade growth-suppressing signals. Cooperating cells have limited lives, but cancer cells resist cell death and hide from an immune system that would typically destroy them. Normal cells distribute nutrients and chemical signals essential to survival, but cancer cells grow extra blood vessels to grab more resources for themselves. These contrasts show us that cheating is not merely a metaphor for cancer. It is a description of cancer's cellular reality.
This lens of evolution and cooperation is providing scientists with new insights into the way cancer happens—and why it does not. Giant animals such as the whale and elephant, for instance, rarely get cancer despite having multitudes of cells that can go wrong. Why? A number of researchers, including our team at Arizona State University's Arizona Cancer Evolution Center, have examined the genomes of these giants and found they have many copies of genes that destroy cells that mutate and produce aberrant proteins, a signal of cancer. The animals also have extra copies of genes that trigger DNA repair. These genes are, essentially, the cooperation police. One of them, called TP53, has been identified as a cancer suppressor in people—but unlike the giant animals, we have only two copies, and unsurprisingly we are more prone to malignancies. Researchers are now trying to translate the actions of such genes into therapies and looking for similar genes all across the tree of life. Oncologists have even started to use evolutionary principles to design chemotherapy that protects less aggressive, less selfish cells within a nascent tumor, reducing the cancer's danger.
The Cooperation Game
I was first drawn to this evolutionary interplay between cooperation and cheating when I was getting my undergraduate and graduate degrees in psychology. I wrote computer programs that tested the effects of different strategies on hypothetical populations, rather like nodes in a network. Generally in such models, without countervailing forces such as genetic relatedness or social norms of reciprocity to keep them in line, cheaters outcompete cooperators. At first I was trying to understand what helps keep cooperation stable in human societies. But then I began learning about the biology behind cancer and the ways cancerous cells behave, and it became clear that lots of cancer cell activities looked like the breakdown of cooperation in a multicellular system. Cancer—which had seemed to me like a senseless disease, an organism destroying itself—started to make sense.
As I looked deeper, I discovered that cellular cheating manifests as cancer and cancerlike phenomena in many complex organisms, from humans to clams to cacti. Plants, for example, exhibit cancerlike protrusions called fasciations. One of the most striking examples is the crested cactus. Saguaro cacti can develop mutations in meristem cells (equivalent to stem cells in animals) on the growing tips of the plant. These lead to cell overproliferation and abnormal growths that fan out into crests. The fasciations can be quite beautiful, but like cancer in people, they can take a toll. Crested cacti often have disrupted flowering, which impairs reproduction, and are more vulnerable to disease and injury.
I realized that many of these breakdowns in cellular cooperation bore an uncanny resemblance to the “hallmarks of cancer,” a framework developed by cancer biologists to describe general tendencies of malignancies. In addition to things such as excess proliferation, invasion of other tissues is one of the hallmarks of cancer, and an evolutionary approach suggests that invasion might be a consequence of cellular cheating. When cancer cells overuse resources in their local environments—producing enzymes that digest nearby tissue, for instance—the process often destroys their normal cellular surroundings. We know from ecology that organisms that deplete resources in their environments are under greater pressure to evolve the ability to move via “dispersal evolution.”
Cancer cells respond to this same pressure to go mobile. I created a model of cancer that showed that higher rates of cellular resource consumption led to the evolution of cells that had a greater propensity to move, a development my colleagues and I reported in 2012 in Cancer Prevention Research. Our conclusion suggested that overuse of resources by cancer cells may be one of the pressures that drives cancer to metastasize, or spread. Even before invasion of other tissues happens, degradation of resources may push cancer cells to evolve the ability to move inside tumors.
This ecological and evolutionary perspective highlights new ways of identifying cancerous cells, beyond the typical hallmarks such as excessive replication. In 2017 biologist Carlo Maley and I, along with other colleagues at Arizona State, noted in Nature Reviews Cancer that scientists can look for cells that are not properly regulating other aspects of their behavior. These features include cells that are consuming resources too quickly or producing proteins and enzymes that damage the environment around them.
The cooperation inside a multicellular body is not just about cells holding back from excessive activity. It is also about other cells working to detect and suppress cheating when it arises. Bodies have evolved ways of doing this. For instance, cells normally can replicate only with “permission” from their neighbors, which trigger the release of growth signals. And if any cells depart from the proper multicellular script, they are targeted for destruction by their cellular neighbors or the immune system.
Cancer cells also cheat detectors in their own genetic code. One such sentinel is the cancer-suppressor gene TP53. It codes for a protein called p53 that plays a central role in many aspects of cellular control, from halting the cell cycle and initiating DNA repair to triggering apoptosis (controlled cell death) if a cell is too damaged. Other genes in our police force include BRCA, a crucial DNA-repair gene; when mutated and unable to perform its normal function, BRCA increases the risk of breast, ovarian and prostate cancer.
Genes in the TP53 family (others include TP63 and TP73, both of which help to maintain the integrity of the genome) evolved very early in multicellular organisms, first appearing in primitive creatures such as sea anemones, and offered enough of a survival advantage to subsequently spread widely across the tree of multicellular life. In 2019 Anna Trigos of the Peter MacCallum Cancer Center in Australia and her colleagues reported that common mutations in cancer overwhelmingly affect signaling pathways that involve genes such as TP53. Furthermore, they found that there was a loss of communication between these genetic regulatory systems that evolved even before the evolution of multicellularity and those that evolved to keep these more selfish cellular behaviors under control during the transition to multicellularity. The scientists figured out the age of the genes using a technique called phylostratigraphy, which compares features of genes of existing organisms to determine a likely common ancestor, ultimately showing where and when in the evolutionary tree of life these genes emerged. They then looked at the mutated genes in tumors from more than 9,000 patients, finding that the genes that help to regulate multicellular cooperation were often compromised.
How do genes such as TP53 spot cheating? They appear to function as information collectors about cellular activity. For example, signals about an increased number of mutations in a cell or heightened production of aberrant proteins flow to these genes from elsewhere in the cell and from other parts of the genome. Such signals most likely indicate that the cell is no longer cooperating properly with the multicellular body. And they trigger action by TP53 and similar genes, which can halt the cell-replication cycle and initiate DNA repair. If these measures are insufficient, the genes induce cellular death to protect the organism from the potential threat that the cell might pose.
The two copies of TP53 in humans come from our parents: one from our mother, one from our father. If one of these copies of TP53 becomes mutated itself, this leads to a much higher overall cancer risk over a person's lifetime. People who have a rare condition called Li-Fraumeni syndrome inherit just one copy of TP53, which leaves them extremely susceptible to cancer.
Elephants, in contrast, have 40 copies of their version of TP53–it is called EP53—and several scientists, including myself, think this explains why the giant animals rarely get cancer. That absence of malignancy has been a long-standing oncological puzzle known as Peto's paradox. In 1977 Richard Peto, an epidemiologist at the University of Oxford, and his colleagues pointed out that larger (and longer-lived) organisms should get more cancer than smaller creatures because bigger ones have more cells and logically that should raise the chances of malignant mutations. Yet cancer risk and body size do not track, he noted. In a study published in 2017 and in ongoing work, our research group has found that this paradox exists throughout the animal kingdom. We created a large database of zoo and veterinary pathology records and learned that species that are larger and longer-lived have essentially the same rates of cancer as species that are smaller and shorter-lived; our continuing analysis has pointed to more instances of this pattern.
To us, this suggests that large and long-lived organisms have particularly good mechanisms for suppressing cellular cheating, such as those extra copies of EP53. Evolutionary geneticists have compared elephant genomes with reconstructed genomes of several related species—the woolly mammoth, for one—and found that as animals in this lineage got bigger, they kept adding more copies of TP53-like genes. This repeated occurrence suggests that the genes played an important role in the evolution of large body size. Big bodies helped the elephants and their kin survive predators, and the cancer-suppressor genes helped the elephants survive cheating cells in those big bodies.
This seems to be a pattern. Jumbo bodies have evolved many times in the history of life, both on the land and in the sea, and genes to check cheaters evolved with them. For instance, among cetaceans, the taxonomic group that includes dolphins and whales, a huge variation in body size exists. The humpback whale is approximately four times larger than the closely related common minke whale, and the orca whale can be 20 times larger than the closely related bottlenose dolphin. And the numbers of genes in the cellular-cooperation police force go up with body size in this group. Members of our research team, looking closely at the genomes of humpback whales, found duplications of genes involved in the process of apoptosis, when cells recognize they can no longer function properly and essentially kill themselves. Smaller cetaceans do not have as many copies of these genes. In the big whales, our group also found evidence of evolutionary selection for a number of genes involved in cancer suppression, such as cell-cycle checkpoint genes, cell-signaling genes and genes involved in proliferation. One of these genes, called PRDM2T, regulates the expression of the cetacean version of TP53, which again shows the central role of that particular sequence of DNA.
Stopping cheating cells is not an easy task, because, in an ironic twist, malignant cells that stop cooperating with normal cells can start to cooperate with one another. That makes things even worse for healthy cells. For example, cancer cells can produce growth factors for one another. They can also help shield their fellow cheaters by producing molecules that help malignant cells cloak themselves, making it harder for immune cells to detect them. My group's computational models of cell populations in the body show that this kind of cancer cooperation can evolve and is more likely to happen when cancer cells interact with their genetic clones, events that often occur in tumors. This cooperation among rule breakers may drive their ability to successfully metastasize and invade other tissues. Cancer cells can move as a group, using electrical and chemical signaling, sometimes forming a long line of cells that works its way into other parts of the body. One study found that groups of tumor cells in the bloodstream are 23 to 50 times more likely to successfully generate metastases compared with individual cancer cells in the blood.
Improving Natural Detection
Cooperating cancer cells do seem like the stuff of nightmares, but understanding the role of cooperation among cells does let us think about new ways of stopping the cheaters, even when they band together. It may be possible, for example, to strengthen our natural cheating-detection systems. Some members of our research center are currently working on developing cancer treatments using elephants' abundant EP53 genes. In test-tube experiments, they have already shown that splicing EP53 into the genome can restore damaged p53 functions in cells taken from human and dog osteosarcomas. The addition of EP53 enhanced the usual apoptosis response that helps to protect the body from cancer cells. Treatments called immune system checkpoint blockades are another exciting area. These drugs block the ability of cancer cells to send misleading signals to immune cells—signals that hide their escalating cheating behavior—and they have shown some success in treating cancers such as melanoma.
Still another approach, called adaptive therapy, tries to weaken groups of cancerous cells by maintaining cells among them that are not so far gone. Instead of bombarding a tumor with heavy doses of chemotherapy—which ultimately favors the evolution of cells that resist the drugs, just as constantly spraying pesticides on crops leads to pesticide-resistant insects—oncologists have been trying a more restrained approach. They employ only enough chemotherapy to keep the tumor small. Allowing drug-sensitive cells to survive and compete for resources with drug-resistant cells can keep the latter population low. In early clinical trials with patients who had aggressive prostate cancer, this method kept tumors under control for at least 34 months, compared with the average for standard therapy of about 13 months. These tests are ongoing.
And because cooperation among cheaters—a warped honor among thieves—seems to be an important strategy among cancer cells, my colleagues and I have proposed blocking the molecules these cheaters pass back and forth as they signal one another to grow or develop new blood vessels to supply tumors. It would make it harder for cancer cells to work together. Given the ability of groups of cells to invade and metastasize more effectively, interfering with molecules that cancer cells use to stick to one another could be another future direction for therapies. Patients who have higher levels of some of these sticky proteins called plakoglobins have more metastases and lower survival rates, suggesting that the proteins are targets worth investigating.
The social lives of cancer cells within the body are much more complex than we could have anticipated. But our normal healthy cells are arguably even more sophisticated, and within them lie many weapons against cells gone rogue. We are not only bastions of cellular cooperation: each and every one of our cells contains within it a complex genetic network that can detect and respond to cheating. We are, after all, descended from a line of multicellular ancestors that suppressed cancer long enough to reproduce, and their offspring carried these traits onward.
In the big picture of the evolution of life, cellular cooperation has been wildly successful despite the persistence of cellular cheating. Cancer may break the body's rules, but we—along with whales and all other forms of multicellular life on this planet, honed by billions of years of natural selection—hold the tools for restoring peaceful coexistence.