The cancer cell next door

We know a lot about what can go wrong inside cells during disease. But what about the healthy bystanders?

Your body is a mosaic of cells, all squished together to form the tissues and organs that allow you to digest, think and breathe. The proper function of these organs depends entirely on the health and behavior of the individual cells that make them up, and disease occurs when cells don’t behave normally. For example, cancer is caused by cells that divide over and over again when they should not. But what happens to the innocent bystanders, the well-behaved cells next door to the troublemakers, during disease?

Scientists have studied the details of misbehaving cells for decades, but more recently, some researchers’ attention has turned to those innocent bystander cells — and revealed a surprisingly fascinating phenomenon. In the case of cancer, we know all about the misbehavers: which genetic mutations predispose cells to divide uncontrollably, how they trick the body into providing them with extra nutrients, and how they squirm out of their original tissue to colonize other parts of the body. But it turns out that the neighboring healthy cells are just as active in their own way. In a process called cell competition, healthy cells surrounding small groups of unhealthy cells can, in some cases, obliterate their dysfunctional neighbors, rescuing a tissue from being overtaken by cancerous growth.

What happens to the innocent bystanders, the well-behaved cells next door to the troublemakers, during disease?

The biologists that first discovered this phenomenon had not set out to study cancer. Instead, they were interested in how organs are formed during embryonic development – a series of complex processes that place cells in the right place to build functional bodies. They used genetic tools in the fruit fly (Drosophila melanogaster) to make small populations of cells that either divided a little too slowly, or small populations of cells that divided a little too quickly, in the wing of the fly. They were hoping that the space these cells took up as the fly wing formed during development would reveal delineations within a tissue called compartment boundaries, mysterious contours that cells never cross during the tumult of development (compartment boundaries are very cool, but material for a future post).

Instead, they found that the slow-growing groups of cells puzzlingly disappeared from the wing as the fly developed, while the fast-growing group of cells quickly replaced the healthy cells to make up the majority of the wing blade. To investigate exactly what was going on with these modified cells, they watched as the cells divided in the tissue under a microscope. Interestingly, they saw that the cells on the periphery of the group – the ones that made contact with the un-modified, healthy cells — started to die if they were slow-growing, or prompted death in their healthy neighbors if they were fast-growing. However, when every cell in the wing bore the same genetic manipulation, making the whole tissue either slow- or fast-growing, the wing was completely fine. It was only when populations with different fitnesses encountered each other in the tissue that the fierce competition for real estate took place. This discovery set off a frenzy of research exploring how healthy cells sense and root out misbehaving neighbors. It’s hard not to anthropomorphize the process, and the scientists who have written about cell competition describe tissues as “social groups that are governed by societal rules”, made up of “winner cells” and “loser cells”.

So, how do cells sense that their neighbors aren’t acting quite right? And how do they perform the macabre act of eliminating them? Much of this is still shrouded in mystery, but we do know that the process requires chemical signals that emanate from all cells. One attractive hypothesis is that the modified slow-growing cells are bad at sucking up chemical signals that tell them to continue to live, while fast-growing cells are particularly good at procuring life-giving chemical signal. Perhaps all cells “compete” for this scarce chemical signal, and cells that aren’t great at taking their fair share don’t survive for long. However, biologists have now compiled a long list of instances in which cells compete, and the underlying mechanisms of competition are likely to be slightly different in each case. Similar to the myriad of ways human beings can be advantaged or disadvantaged during their lives within a society, cell survival seems to be quite complex and combinatorial. Once again the analogy of tissues working as a “society” holds water.

What is so captivating about the phenomenon of cell competition is the fact that it reveals cells to be actors within a very complex environment. Your tissues and organs are not quiet swaths of drone-like cells; they are dynamic and defined by many, many interactions between the cells that make them up. Taken together, these interactions serve to build the most robust tissue possible, by eliminating weak or sick cells. Equipped with this new view of cellular communities, scientists are hopeful that by studying what happens at the early stages of cell competition, we might understand the historically mysterious earliest stages of cancer.

Your tissues and organs are not quiet swaths of drone-like cells; they are dynamic and defined by many, many interactions between the cells that make them up.

In fact, you might have noticed by now that there are tantalizing parallels between cell competition and start of cancerous growth. Many of the genetic modifications that give cells a competitive advantage in a tissue, allowing them to kill off healthy cells, are also modified in cancer cells. A study in 2016 carefully tracked the early behavior of these “super-competitive” cells in the gut of the fruit fly. They found that only when the group of modified cells reached a certain size – roughly 30 cells – did they induce death in their neighbors. Next, the group, along with scientists who were studying the same phenomenon with different types of genetic modifications, did something incredible. Instead of killing or removing the tissue afflicted with the modified cells, which is a common method of combating cancer, the scientists blocked cell death in the tissue. Unable to out-compete their neighbors, the fast-growing, pre-cancerous cells failed to overtake the tissue.

More and more, biologists are turning to the healthy cells in our bodies to identify and eradicate their sick counterparts, with promising results. By endowing the healthy cells with quasi-immortal status, the scientists were able to deny the fast-growing cells their competitive advantage, and rescued the tissue from cancer.

However, none of this groundbreaking work could have happened without initial studies on the basic biology of how cells work together to build tissues and organs. What started out as observations of fruit fly wings led, surprisingly, to a deeper understanding of cancer and enabled us to harness the tools our cells are already endowed with to fight it.

Featured image courtesy of the Cell Image Library.

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