Buildup of random mutations in adult stem cells doesn’t explain varying frequency of cancers

To divide or not to divide?

 It’s a question every cell in your body must constantly ask itself. Cells in your small intestine, for instance, replace themselves about every three days so the cells in that tissue must divide frequently to replenish the tissue. Liver cell are less active and turn over about once a year. And on the other extreme, the cells in the lens of the eye are kept over a life time.

The cell cycle, an exquisitely controlled process.

The cell cycle, an exquisitely controlled process. (Source wikipedia)

It’s no wonder that the process of cell division, also called the cell cycle, is exquisitely controlled by many different proteins and signaling molecules. It also makes sense that mutations in genes that produce the cell cycle proteins, could cause the regulation of cell division to go awry.

Mutations pave a path to cancer

Accumulation of enough mutations over a lifetime can lead to uncontrolled cell growth and eventually cancer. Adult stem cells are thought to be especially vulnerable to cell cycle mutations since these cells already have the capacity to self-renew and can pass mutations to their daughter cells.

Now, gene mutations can be inherited from one’s parents or caused by environmental factors like UV rays from the sun or acquired by random mistakes that occur as DNA replicates itself during cells division. Studying how the accumulation of these different mutation types impact cell division is important for understanding the formation of cancers. Results from a study in early 2015 indicated that mutations caused by random mistakes in DNA replication had a bigger impact on many cancers than mutations arising from lifestyle and environmental factors.

“Bad luck” mutations may not be the most harmful

But a new research publication in Nature suggests that, while these “bad luck” mutations can drive the development of cancer, they probably are not the main contributors. To reach this conclusion, the research team – which hails from the University Medical Center Utrecht in the Netherlands – directly measured mutation rates in human adult stem cells collected from donors as young as three years and as old as 87. In particular, stem cells from the liver, small intestine and colon were obtained. Individual stem cells were grown in the lab into mini-organs, or organoids, that resemble the structures of the source tissue. After studying these organoids, they determined that the frequency of cancer is very different in these organs, with the incidence cancer in the colon being much higher than in the other two organs.

Mutation rate the same, despite age, despite organ type

Through a various genetic analyses, the team found that an interesting pattern: the mutation rate was the same – about 40 mutations per year – for all organ types and all ages despite the higher incidence of colon cancer and older age-related cancers. Dr. Ruben van Boxtel, the team leader, expressed his reaction to these results in an interview with Medical News Today:

“We were surprised to find roughly the same mutation rate in stem cells from organs with different cancer incidence. This suggests that simply the gradual accumulation of more and more ‘bad luck’ DNA errors over time cannot explain the difference we see in cancer incidence – at least for some cancers.”

Still, the team did observe that different types of random mutations were specific to one organ over the other. These differences may help explain why the colon, for example, has a higher cancer incidence than the liver or small intestine. Van Boxtel and his team are interested in examining this result further:

“It seems ‘bad luck’ is definitely part of the story but we need much more evidence to find out how, and to what extent. This is what we want to focus on next.”

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