The inability of chromosomes to be properly distributed during cell division is one of the abnormal characteristics of cancer cells. Now, scientists have discovered that cancer cells confined within narrow microscopic channels can develop a unique problem with the chromosome distribution mechanism, but strangely, increasing physical limitations can suppress these abnormalities. The effects of this type of confinement are similar to the crowding of cells surrounding a tumor, and the researchers hope their findings will shed light on the cancer's causes and possible solutions.
Studying Cell Division
After the genome is copied, the chromosomes split into two groups in a healthy, dividing cell. Both groups are attached to the mitotic spindle, a collection of arranged microtubules compressed into pole-like structures at their ends. The chromosomes are then pulled towards the poles along the microtubules. The development of more than two pole spindle fibers is a major contributor to false chromosomal segregation in cancer cells. In vivo, multipolar spindle production may differ from phenomena observed in cells cultured in a dish, so it is possible that the restrictive effect of surrounding cells in a tissue has some influence on this process.
Chromosomes Are Not Distributed Properly When Cancer Cells Divide
To study the effect of a restrictive environment, Hongyuan Jiang of the China University of Science and Technology and colleagues cultured human cancer cells by placing them in channels within microscopic channels in a plastic sheet on a glass slide. If the paths were wide and deep enough, the cells could expand without coming into contact with the walls. However, if the channels are shallower than 20 µm, the cells are surrounded by the "floor" and the "ceiling". Also, if the channels were narrower than 20 µm, the cells were pushed against the channel sidewalls. The four-walled cells were therefore constrained in channels smaller than 20 μm in both width and depth, causing them to grow in an elongated manner.
The morphologies of the mitotic spindles of the cells were significantly different from the two types of restriction, two-walled and four-walled. These cancer cells display a significant frequency (about 12%) of three to five (or sometimes more) pole spindles when allowed to grow freely and unconstrained. However, for channels 3 μm deep, the two-walled restriction increased this occurrence to over 60%.
This result is consistent with past research showing that micro-restricted cancer cells can often give rise to large numbers of daughter cells with chromosomal abnormalities.
A different situation arises when there are four walls in smaller channels.
At channel widths of 22-30 μm, approximately 10% of the cells in channels with a depth of 10 m contained multipolar spindles, while at channel widths of 8-12 μm this proportion decreased to only 4%.
This sounds weird:
If some restraint encourages, why would more restraint hinder the development of multipolar spindles?
According to Jiang and his colleagues, it depends on how easily the two poles converge or a single pole splits. To better understand these processes, they developed a simple model that treats poles like tiny objects that can attract or repel each other. The model also takes into account interactions between the interior of the cell membrane and the poles. These interactions are critical in the case of four-walled confinement, which causes cells to elongate and brings the poles closer to the cell membrane on average. This proximity to the membrane changes the energy balance of pole-pole interactions, increasing the probability of pole aggregation and reducing the probability of pole splitting, which in turn reduces multipolarity.
According to mathematical biologist Alex Mogilner of New York University, “their topic is very relevant to biomedical applications” because many cancer cells as well as healthy cells form inappropriately multipolar spindles and divide. “This is indeed the first study to show directly how important cell structure is. It is an excellent example of a physical bottom-up approach to a challenging biological issue. According to Yale University biophysicist Jonathan Howard, the results also "emphasize how little we know about spindle multipolarity."
It is not yet clear whether the findings will result in new approaches to tumor suppression. Joachim Rädler, a soft matter physicist at Ludwig Maximilian University in Munich, warns that it will be difficult to translate findings from lab-grown cells into treatments for humans. Jiang is optimistic though. He claims that controlling the degree of solitary confinement in a tumor “could be a possible technique for cancer prevention and treatment.” “Multipolar spindles promote progression of cancer to more malignant types.”
Günceleme: 11/03/2023 12:45