Squeezed Cells Behave Badly

Squeezed Cells Behave Badly
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It's no secret that people behave strangely when they are confined to small spaces. Just ask anyone who's ever been crammed in an elevator or sandwiched in the back seat on a long car ride. But did you know that cells can also act badly when they're cooped up?

In a new study published in PLoS ONE, researchers show that HeLa cells (a cancerous cell line) behave very strangely when they are limited to a small growing space. Specifically, they showed that mitosis (cellular replication) is adversely affected by this confinement.

The researchers' choice to study confined cells is unique in that it focuses on the cells' mechanical environment (things that physically poke and prod the cell) rather than their chemical environment (proteins and molecules that interact with the cell).

"The majority of what scientists know about cancer and cell biology is based on biochemical processes," said Dino Di Carlo, the research team's leader, via email. "Not until recently have investigators turned their attention to the ability of cells to sense mechanical forces that can modulate their phenotype."

But more important than the novel nature of the study is its possible application to human health. The mechanical forces of confinement are designed to mimic the over-crowded conditions of cells growing in a tumor. Therefore, the results of this study could contribute to what we know about tumor growth.

To simulate tumor cells' limited space, the researchers constructed a membrane outfitted with rows of precisely-spaced posts—similar to a flat, flexible Lego. They put the "Lego" post-side down onto the culture surface so that the cells were forced to grow between the posts.

As the cells began to grow in their confined environment, researchers found the cells' replication was abnormal. Confined cells were more likely to die, took longer to replicate, and divided unevenly more often than unconfined cells. But the strangest observation was that confined cells sometimes produced three, four, or even five daughter cells, rather than the usual two.

This observation was quite pronounced. In the treatment where the cells were most confined, about half of all replications observed resulted in more than two daughter cells. What's more, the daughter cells were still viable and were able to replicate to produce daughter cells of their own.

The researchers posit that the cells' cramped living quarters could have caused this multi-daughter replication by giving the cells an oblong shape. This shape may have made it difficult for the cell's microtubules to properly move the chromosomes to opposite ends of the cell during mitosis. Instead, the chromosomes might have been pulled in all directions, resulting in three, four, or five daughter cells. 

According to the researchers, it's highly likely that the daughter cells end up with different numbers of chromosomes when this abnormal replication occurs. Scientists have known for a long time that cancer cells often contain an abnormal number of chromosomes, but they are still trying to find out why. This study suggests that mechanical confinement could be a contributing factor.

Di Carlo says that one of the team's future goals is to figure out how exactly the mechanical environment is related to tumor growth. While their current study shows that tumor-like confinement causes abnormal cell replication, the researchers aren't sure which stage of tumor growth they are simulating.

Furthermore, it should be noted that the HeLa cells used in this study are a cancerous cell line, so they have genetic abnormalities that normal human cells don't have. Di Carlo explained that when normal cells were tested in the confined environment, they were not able to complete replication and simply died. It seems that in order to develop the replication abnormalities observed in this experiment, the cells might require innate genetic problems that make them more susceptible to outside forces like confinement.

"We hope to determine if mechanical confinement is either an initiator of tumor formation (i.e. normal cells becoming cancerous), or if confinement acts synergistically with previously identified tumorigenic milestones (such as genetic mutation) to increase the rate of tumorigenesis," said Di Carlo. "Whether in the end it is initiation, accelerated progression, or a combination of these, we believe that mechanical confinement plays a significant role in proper maintenance of cycling cells in human tissues."

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