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Unmasking the chimera

New study explores link between chimerism and cancer

Illustration of multicolored butterflies.

The emergence of multicellularity marked a significant evolutionary milestone, introducing a new level of biological complexity and enabling the formation of a vast array of organisms. This transition allowed individual cells to specialize, work in cooperation, and collectively perform functions that single cells could not achieve, paving the way for the development of complex life forms. Foreign cells can occasionally take up residence within such multicellular organisms, leading to a phenomenon known as chimerism. Graphic by Jason Drees

June 29, 2023

Although humans tend to view personal identity as their most valued possession, biology teaches us that the truth is far from straightforward. At the core of our being, we are all chimeric entities — biological composites composed not just of our own cells, but also cells that are not "us" in the conventional sense.

Chimerism — the presence of genetically distinct cells within a single individual — is not restricted to humans or even mammals but can be found in various forms across the tree of life. The word chimera originally referred to a monster from Greek mythology with a lion’s head, a goat’s body and a snake’s tail.

In a new study, researcher Stefania Kapsetaki and her colleagues explore the relationship of chimerism across an array of multicellular species and the invasiveness of tumors found in these organisms. The study reveals that multicellular organisms displaying greater chimerism — that is, those that are more permissive of foreign cells — may have cancers that are more invasive. In particular, the study demonstrates that tumor invasiveness is closely correlated with the presence of genetically different cells.

The study is the first to begin to tease out the complex relationships between cancer and chimerism and may point the way to improved techniques for short-circuiting the deadly disease. The research promises to deepen insights into the phenomena of transmissible cancers. It also opens the door to a better understanding of one of the most perplexing phenomena in nature and a mystery science has only begun to explore.

“Chimerism appears to be an additional piece in the puzzle of explaining the variation in tumor invasiveness across the tree of life,” Kapsetaki said. “The exact mechanisms connecting chimerism and cancer are unknown for every species and require further investigation.”  

Kapsetaki is a postdoctoral alumnus with Arizona State University's Biodesign Center for Biocomputing, Security and Society and the Arizona Cancer Evolution Center. She is joined by ASU colleagues as well as researchers from North Carolina State University and the University of California, Santa Barbara. Kapsetaki has recently joined the research staff at Tufts University.

The study was carried out at ASU in conjunction with the Arizona Cancer Evolution Center, and directed by Carlo Maley, a co-author of the new paper. He is also a researcher with the Biodesign Center for Biocomputing, Security and Society and a professor with the School of Life Sciences.  

The research appears in the current issue of the journal PLOS ONE

Stefania Kapsetaki

Symbiosis and struggle: Dual faces of chimerism

During a shadowy phase of evolutionary history, single-celled organisms took a momentous leap. Choosing cooperation over autonomy, these free-living cells began forming symbiotic collectives, marking the rise of multicellularity. This epoch-making shift in the way life organizes itself led to an explosive proliferation of multicellular life forms, including the vast array of plant and animal species we see today, humans among them.

But even as these multicellular entities evolved, they retained a biological heritage from their single-celled ancestors. This manifests in the form of chimerism, the presence of genetically distinct cells within a single organism.

The origins of these nonself cells are varied. Some are introduced into our bodies from other individuals of the same species. This can happen naturally, for instance, during pregnancy, when cells from the fetus can cross the placenta and establish a lasting presence in the mother's body, a phenomenon known as fetal microchimerism.

There has been much speculation regarding these chimeric cells, which have been found throughout the bodies of pregnant women, including in their brains, where they may act to alter the behavior of the mother. Fetuses are known to compete with the mother for limited resources but migrating fetal cells may also be involved in the processes of mother-child bonding or other yet-to-be-discovered phenomena.

Carlo Maley

Spread of chimerism in nature

While our identities may be uniquely our own, our bodies tell a story of shared biological heritage and intermingled existence. From genetically distinct entities in marine sponges and trees, to the fusion of different colonies in tunicates (sea squirts), life has myriad ways of blurring the boundaries of individuality.

Most animals, including humans, have cells that are specialized to perform different functions that must work together for the organism to survive. They are known as obligately multicellular. In contrast, many unicellular organisms like bacteria and yeasts are facultatively multicellular, meaning they can exist as single cells, but they can also form multicellular structures when necessary, such as in response to environmental stress or during certain stages of their life cycles.

In addition to fetal microchimerism in humans, chimeric events are common across a broad variety of species. Many plants can naturally graft onto each other and share vascular tissues, which can result in chimerism. Certain trees have been known to naturally graft their roots together, forming a network of interconnected individuals.

Chimerism has been observed in several species of reptiles, birds and mammals. This can occur naturally (for instance, in the case of twin animals whose cells mix in the womb) or artificially (as in the case of animals that have received organ transplants).

Chimera’s dark reflection

There are several potential evolutionary advantages to chimerism. It can increase genetic diversity within an organism, providing a wider range of traits that might be beneficial in adapting to changing environmental conditions. In some circumstances, organisms can share resources across genetically distinct individuals, potentially enhancing survival and growth, a phenomenon observed in some marine invertebrates. Chimerism in mammals can lead to a more diverse immune system, potentially enhancing the ability to resist infectious agents.

Nevertheless, the incorporation of nonself cells in an organism carries the risk of disease, including cancer.

Chimeras and cancers share some common hallmarks. Both can evade immune destruction, inducing angiogenesis and invasion. In fact, chimeric fetal cells have been found in several tumors in mothers — more often in cancerous tissue than in healthy tissue.

This suggests that chimerism may be linked to an increased susceptibility to invasion by cancerous cells, but not necessarily to the development of cancer itself. This finding might be valuable in further understanding the mechanisms that underlie invasive cancers, and it could also potentially inform the detection and management of emerging transmissible cancers.

In this study, researchers classified 12 different obligately multicellular species based on their levels of chimerism, as reported in existing literature.

Next, they tested for a correlation between chimerism and various factors related to cancer, such as tumor invasiveness, the prevalence of neoplasia (benign or malignant growth) and the prevalence of malignancies. The results indicated that species with higher levels of chimerism tended to have higher levels of tumor invasiveness. However, there was no observed correlation between the level of chimerism and either neoplasia or malignancy rates among mammals.

The study suggests that there may be an important biological relationship between chimerism and susceptibility to tissue invasion by cancerous cells. The findings imply that species most accepting of foreign cells (i.e., nonmicrobial cells) are likely to harbor transmissible cancers.

"We are getting the first hints of a connection between an organism’s tolerance for genetically different cells and its tolerance for the genetically abnormal cells that evolve in cancers," Maley said. "This is a start, but a lot more work needs to be done to measure chimerism across species."

Unraveling the mechanisms used by foreign cells to invade and become irreplaceable parts of chimeric multicellular organisms might aid in finding similar mechanisms in cancer cells, leading to the development of new drugs to combat these pathways or other means of managing the disease.

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