USA - Bioengineers discover single cancer cell can produce up to five daughter cells

Conventional biology expects the process of mammalian cell division, mitosis, to occur by the equal partition of a mother cell into two daughter cells. Bioengineers at UCLA Engineering have developed a platform that mechanically confines cells, simulating the in vivo three-dimensional environments in which they divide. Upon confinement they have discovered that cancer cells can divide a large percentage of the time into three or more daughter cells instead.

It's well known in conventional biology that during the process of mammalian cell division, or mitosis, a mother cell divides equally into two daughter cells. But when it comes to cancer, say UCLA researchers, mother cells may be far more prolific.

Bioengineers at the UCLA Henry Samueli School of Engineering and Applied Science developed a platform to mechanically confine cells, simulating the in vivo three-dimensional environments in which they divide, and found that, upon confinement, cancer cells often split into three or more daughter cells.

"We hope that this platform will allow us to better understand how the 3-D mechanical environment may play a role in the progression of a benign tumorinto a malignant tumor that kills," said Dino Di Carlo, an associate professor of bioengineering at UCLA and principal investigator on the research.

The biological process of mitosis is tightly regulated by specific biochemical checkpoints to ensure that each daughter cell receives an equal set of sub-cellular materials, such as chromosomes or organelles, to create new cells properly.

However, when these checkpoints are miscued, the mistakes can have detrimental consequences. One key component is chromosomal count: When a new cell acquires extra chromosomes or loses chromosomes — known as aneuploidy — the regulation of important biological processes can be disrupted, a key characteristic of many invasive cancers. A cell that divides into more than two daughter cells undergoes a complex choreography of chromosomal motion that can result in aneuploidy.

By investigating the contributing factors that lead to mismanagement during the process of chromosome segregation, scientists may better understand the progression of cancer, said the researchers, whose findings were recently published online in the peer-reviewed journal PLoS ONE.

For the study, the UCLA team created a microfluidic platform to mechanically confine cancer cells to study the effects of 3-D microenvironments on mitosis events. The platform allowed for high-resolution, single-cell microscopic observations as the cells grew and divided. This platform, the researchers said, enabled them to better mimic the in vivo conditions of a tumor's space-constrained growth in 3-D environments — in contrast to traditionally used culture flasks.

Surprisingly, the team observed that such confinement resulted in the abnormal division of a single cancer cell into three or four daughter cells at a much higher rate than typical. And a few times, they observed a single cell splitting into five daughter cells during a single division event, likely leading to aneuploid daughter cells.

"Even though cancer can arise from a set of precise mutations, the majority of malignant tumors possess aneuploid cells, and the reason for this is still an open question," said Di Carlo, who is also a member of the California NanoSystems Institute at UCLA. "Our new microfluidic platform offers a more reliable way for researchers to study how the unique tumor environment may contribute to aneuploidy."

Journal reference: PLoS ONE   

Provided by University of California, Los Angeles

http://phys.org/

Singapore - Molecular biology: Preventing cell division

Livers from Cdk1 knockout (KO) mice (bottom row) display fewer but larger cells compared to wild type (WT) mice (top row), both before and after partial hepatectomy (PH)

One of the enzymes known to regulate the cell cycle has now been shown to play a key role in mitosis

Cyclin-dependent kinase 1 (Cdk1) is a member of the Cdk family of enzymes which control the cell cycle. Philipp Kaldis at the A*STAR Institute of Molecular and Cell Biology and co-workers1 have now shown that Cdk1 plays a critical role in cell division. Moreover, the researchers discovered that by inactivating Cdk1 production, they could prevent tumor formation in mice. The new finding may open up new avenues in the development of cancer drugs and treatment.

In the mammalian genome, there exist more than 20 different Cdks that regulate different phases of the cycle of cell division, or mitosis. Previous studies have shown that mice with any one of these genes knocked out remain viable, suggesting that enzymes of the Cdk family have overlapping roles. Due to technical difficulties, however, no knockout mice for Cdk1 have so far been developed. Now, Kaldis and co-workers have not only generated Cdk1-knockout mice, but also developed adult mice in which active Cdk1 genes could be switched off by chemical means.

The researchers found in their experiment that mice lacking functional Cdk1 genes die within three and a half days of conception. Their embryos also display fewer but larger cells. The researchers suggest the cells in very-early-stage embryos contain remnants of the products of the mother’s Cdk1 genes, which allows them to carry out limited cell division. Without Cdk1, the cells cannot divide and will instead continue to grow, suggesting that Cdk1 is critical to mitosis.

The researchers studied the role of Cdk1 in liver regeneration in adult mice. They found that of all the organs in the mammalian body, the liver could tolerate the loss of Cdk1 the most as its cells only divide in adulthood during regeneration. They made use of experimental animals whose livers were deficient in Cdk1. When they surgically removed part of the livers, the researchers found that regeneration still took place, not by producing more cells, but by increasing the size of existing cells.

The researchers also studied the impact of loss of Cdk1 activity on the generation of tumors, both in cell culture and in the livers of adult mice injected with carcinogens. They discovered that without Cdk1, tumor cells could not proliferate.

“We are now able to delete Cdk1 in any tissue or tumor type we choose at any time point,” says Kaldis. “So our mouse model offers a neat method to test whether drugs targeting Cdk1 activity can be effective in treating cancers.”

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology

References

1. Diril, M. K. et al. Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proceedings of the National Academy Sciences USA 109, 3826–3831 (2012). | article