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Section of human colon showing sausage-shaped crypts. The section has been stained for a protein called MAOA (shown in brown). The blue crypt carries a fault in the MAOA gene, which stops the protein being made and means the crypt no longer shows up as brown. Image courtesy of Winton lab. 

This entry is part 23 of 23 in the series Science Snaps

Cora Olpe is a PhD student at the Cancer Research UK Cambridge institute, working with Dr Doug Winton. She’s interested in how gut stem cells acquire faults over time and how these spread to generate large mutated areas, which could promote cancer. 

In this guest post, she writes about her lab’s work to uncover how bowel cancer develops. 

The human bowel is a long tube coated in a single layer of cells, which bunches up and forms pockets called crypts.

This single layer of cells is exposed to a lot throughout the day and dead cells are constantly being removed from the body and replaced, thanks to special stem cells that live at the bottom of the crypts.

And buried in these crypts could be clues to how bowel cancer develops.

Scientists believe that bowel cancers are born from these stem cells. If stem cells develop faults in their DNA that make them divide more than they should, they can become growing clump of cells that can be identified first as a polyp and later as a tumour. And in some cases, these growths will become cancerous.

So, to understand how bowel cancer develops, we need to study how normal stem cells work and how they become faulty.

Hunting for faulty crypts

First, we need a way to highlight crypts that have DNA faults.

Each cell’s DNA carries the information to make proteins. Some faults can stop the cell producing a protein. So, by ‘painting’ certain proteins in brown, using a method called immunohistochemistry, we can detect when they’re absent, as a blue background colour is revealed.  You can see this in the image below.

Section of human colon stained for a protein called MAOA (shown in brown). The blue crypt carries a fault in the MAOA gene, which stops the protein being made and means the crypt no longer shows up as brown. With this method we can follow the spread of mutations without looking at the cells' DNA.

Section of human colon stained for a protein called MAOA (shown in brown). The blue crypt carries a fault in the MAOA gene, which stops the protein being made and means the crypt no longer shows up as brown. With this method we can follow the spread of mutations without looking at the cells’ DNA. Image courtesy of Winton lab. 

The blue crypts carry our fault of interest. I still remember the first time I saw one of the blue crypts among the crowd of brown. It was electrifying.

Using this technique, we went on to paint lots of healthy bowel samples from people aged 8 – 93 years and then counted the number of blue crypts.

It was a bit of a microscopy marathon, but what we found was exciting.

Accumulating faults

We found that bowel samples from older people had more mutant crypts than those of younger people. So as we age, we accumulate faults in the stem cells in our bowels.

But what was more interesting was how the mutant crypts divide. Typically, individual cells in our body will divide. But we found that the mutant crypts seem to do something different. It looks like they undergo a process called fission, where the whole crypt splits in two.

This creates patches of mutant crypts in the lining of the bowel, as can be seen in the image below.

Section of human colon stained for a protein called MAOA (shown in brown). The blue crypts carry a fault in the MAOA gene, which stops the protein being made and means the crypt no longer shows up as brown. We think the fault appears in one crypt which then divides again and again (in a process called "fission") to form patches of mutant crypts.

Section of human colon stained for a protein called MAOA (shown in brown). The blue crypts carry a fault in the MAOA gene, which stops the protein being made and means the crypt no longer shows up as brown. We think the fault appears in one crypt which then divides again and again (in a process called “fission”) to form patches of mutant crypts. Image courtesy of Winton lab. 

Different gene faults affect these processes in different ways. Some barely generate patches. Others, like those in the cancer-promoting gene KRAS, seem to strongly affect fission to create large patches of 100 or more mutant crypts.

This could be important for cancer, as the more mutant crypts you have, the greater the chance that cells within those crypts will develop extra mutations that could lead to cancer.

Changing the story

We also found large variation in the number of mutant crypts among the different samples we looked at. This may suggest that lifestyle could be affecting how the stem cells behave and acquire DNA faults. Equally, a person’s genetics may also play a role.

We don’t yet have the answers to this, but we’re digging deeper into the data to find out if stem cells found in the bowel behave differently depending on factors like smoking, alcohol and obesity. We’re also using DNA sequencing to look at genetic variation between people’s samples.

Together, this data will help us to understand why bowel cancer affects some people and not others.

Cora Olpe is a PhD student at the Cancer Research UK Cambridge Institute

Reference

Nicholson et al. (2018) Fixation and spread of somatic mutations in adult human colonic epithelium. Cell Stem Cell. DOI: 10.1016/j.stem.2018.04.020

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