It’s a cell-eat-cell world out there—and not just for single-celled organisms. Indeed, even people have something of the cannibal in their cells, even cells that have nothing to do with malignancy or immune function.

What we know about cell-eat-cell phenomena—or, more generally, cell-in-cell phenomena—has been reviewed by scientists based at Arizona State University. They performed a systematic screening of 508 articles, from which they chose 115 relevant articles in a search for cell-in-cell events across the tree of life, the age of cell-in-cell-related genes, and whether cell-in-cell events are associated with normal multicellular development or cancer.

The scientists, led by Carlo C. Maley, PhD, director of the Arizona Cancer and Evolution Center, presented their findings in Scientific Reports, in a paper titled, “Cell-in-cell phenomena across the tree of life.”

“Cell-in-cell events are found across the tree of life, from some unicellular to many multicellular organisms, including non-neoplastic and neoplastic tissue,” the article’s authors wrote. “Additionally, out of the 38 cell-in-cell-related genes found in the literature, 14 genes were over 2.2 billion years old, that is, older than the common ancestor of some facultatively multicellular taxa. All of this suggests that cell-in-cell events may have originated before the origins of obligate multicellularity.”

The widespread occurrence of interactions in which cells become internalized by other cells suggests that these events are not inherently “selfish” or “cancerous.” Rather, it appears that cell-in-cell phenomena may play crucial roles in normal development, homeostasis, and stress response across a wide range of organisms.

“[Our] results show that cell-in-cell events exist in obligate multicellular organisms, but are not a defining feature of them,” the scientists emphasized. “The idea of eradicating cell-in-cell events from obligate multicellular organisms as a way of treating cancer, without considering that cell-in-cell events are also part of normal development, should be abandoned.”

By demonstrating that occurrences span a wide array of life forms and are deeply rooted in our genetic makeup, the research invites us to reconsider fundamental concepts of cellular cooperation, competition, and the intricate nature of multicellularity. The study opens new avenues for research in evolutionary biology, oncology, and regenerative medicine.

“We first got into this work because we learned that cells don’t just compete for resources—they actively kill and eat each other,” Maley said. “That’s a fascinating aspect of the ecology of cancer cells. But further exploration revealed that these phenomena happen in normal cells, and sometimes neither cell dies, resulting in an entirely new type of hybrid cell.”

The study describes 16 different taxonomic groups in which cell-in-cell behavior is found to occur. The cell-in-cell events were classified into six distinct categories based on the degree of relatedness between the host and prey cells, as well as the outcome of the interaction (whether one or both cells survived).

A spectrum of cell-in-cell behaviors is highlighted in the study, ranging from completely selfish acts, where one cell kills and consumes another, to more cooperative interactions, where both cells remain alive. For example, the researchers found evidence of “heterospecific killing,” where a cell engulfs and kills a cell of a different species, across a wide range of unicellular, facultatively multicellular, and obligate multicellular organisms. In contrast, “conspecific killing,” where a cell consumes another cell of the same species, was less common, observed in only three of the seven major taxonomic groups examined.

In addition to cataloging the diverse cell-in-cell behaviors, the researchers also investigated the evolutionary origins of the genes involved in these processes. Surprisingly, they found that many of the key cell-in-cell genes emerged long before the evolution of obligate multicellularity.

“When we look at genes associated with known cell-in-cell mechanisms in species that diverged from the human lineage a very long time ago, it turns out that the human orthologs (genes that evolved from a common ancestral gene) are typically associated with normal functions of multicellularity, like immune surveillance,” said study co-author Luis Cisneros, PhD, formerly a research assistant professor at Arizona State University and currently a research associate at Mayo Clinic.

The ancient cell-in-cell genes identified in the study are involved in a variety of cellular processes, including cell–cell adhesion, phagocytosis (engulfment), intracellular killing of pathogens, and regulation of energy metabolism. This diversity of functions indicates that cell-in-cell events likely served important roles even in single-celled and simple multicellular organisms well before the emergence of complex multicellular life.

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