Bowel cancer cells forget which way is ‘up’

Bowel tissue, showing tumours developing. Credit: N. Barker

The cells in our bodies are highly organised – from our lungs to our liver, every cell knows its place and its job, helping to keep us healthy. But cancer cells don’t obey the rules – they ignore the body’s regulations and grow out of control.

Now research from Dr Inke Nathke and her team at the University of Dundee makes an important step forward in understanding why this happens, in a recent paper published in the journal Cell Stem Cell.

Easy as APC

Dr Nathke is a leading expert on the biology of cells in the bowel. Every single one of the millions of cells lining your bowel is replaced every two to five days – an impressive phenomenon driven by stem cells.

Bowel stem cells divide in two to form another stem cell, and one brand new bowel lining cell – or ‘epithelial’ cell.  The lining cells do their job absorbing nutrients from food and are shed after a few days, while the stem cells keep up the cell ‘production line’.

Dr Nathke’s work focuses on a gene called APC, first discovered by Cancer Research UK scientists back in the 1980s. It’s involved in many aspects of cell growth, and we still don’t entirely understand how it works. But we do know that faults in APC are thought to be a critical step in the development of bowel cancer.

Cancer Research UK scientists, along with colleagues in the Netherlands recently discovered that APC plays an important role in controlling bowel stem cells. When it’s lost in these cells, they rapidly grow out of control and form tumours.  But how does APC normally act to keep stem cells well-behaved?

Looking in 3-D

Until recently, it’s only been possible to look at cells growing in flat layers in plastic dishes in the lab (i.e. ‘two dimensional’ microscopy). But advances in technology mean that scientists can now study cells buried within deep layers of living tissue.

To understand more about APCs involvement in stem cells, the researchers used cutting-edge “three-dimensional” microscopes to study bowel tissue taken from humans and mice either carrying faulty, cancer-causing APC or a working version of the gene.  And they noticed something intriguing.

Dividing in one direction

All cells divide by erecting molecular ‘scaffolding’ around their nucleus, in a structure called the spindle. This provides a frame upon which to divide newly-copied DNA between the two new cells (there’s more about cell division and the spindle on our website – including an explanatory animation here).

When they looked at the 3D structure of the growing bowel cells, the researchers discovered that in all the healthy stem cells, the spindle was always lined up at right-angles to the wall of the gut. This meant that new cells lined up from the outside towards the centre of the gut. The outermost cell (nearest the gut wall) remained as a stem cell, while the innermost cell became a bowel lining cell.

This alignment means that new lining cells are always created facing in the right direction, towards the centre of the gut tube. They get pushed forward by more new cells being made by the stem cell behind them, and eventually are shed into the bowel.

But Dr Nathke and her team noticed something very different about the stem cells lacking APC. Their spindles didn’t line up neatly with each other – instead, the cells divided in all directions, making a disorganised mess of cells with pre-cancerous characteristics. Here’s a simple diagram showing what they saw (click the image to enlarge it):

But this wasn’t the only strange thing they noticed.

Dividing up DNA

When cells divide, they copy all their DNA and distribute it between the two new cells.  In many cases, each cell gets a mixture of ‘old’ and ‘new’ DNA. But this isn’t always the case in stem cells – some scientists have proposed an “immortal strand hypothesis”, in which the ‘template’ (i.e. old) DNA stays in the stem cell, while the new copy gets passed onto the other daughter cell.

To find out whether this was happening in the bowel, the researchers used a chemical to label the DNA in bowel stem cells.  Looking at healthy bowel tissue down the microscope, they saw that stem cells mostly kept their ‘old’ DNA, while the lining cells they produced mainly got freshly made DNA.

But in bowel tissue lacking APC, the old and new DNA was mixed up and shared out equally between the bowel stem cells and the lining cells. And the cells were an unusual shape, compared with cells in healthy bowels.

Where next?

Dr Nathke’s results suggest that bowel stem cells that carry faulty APC genes have ‘forgotten’ how to behave, dividing in all directions and failing to distribute their DNA correctly as they do – typical characteristics of cancer cells.

But there are still many unanswered questions. How does APC help to control the direction of the spindle and make sure the cells divide the right way up? And how does it help stem cells to segregate their DNA correctly when they divide?

It’s unlikely that APC is working alone.  The challenge now is to discover the identities of the other proteins involved, and whether faults in these can also contribute to the development of bowel cancer.

While this research doesn’t directly point us towards any new treatments for bowel cancer, it helps us to unpick the molecular ‘nuts and bolts’ that underpin the disease. And it’s this biological knowledge that opens the door to future treatments for cancer.

Kat

Reference:
Quyn, A. et al. (2010). Spindle Orientation Bias in Gut Epithelial Stem Cell Compartments Is Lost in Precancerous Tissue Cell Stem Cell, 6 (2), 175-181 DOI: 10.1016/j.stem.2009.12.007