Life in the balance - stemming intestinal disease and bowel cancer

Professor Helen Abud studies the delicate balancing act that goes on in our intestine, where stem cells help replace our intestinal lining every few days. Overactive stem cells here can lead to bowel cancer and underactive cells to a loss of intestinal lining. Helen is trying to stop these cells causing damage and use them to repair it.

Our intestine helps us extract nutrients from food and get rid of the waste. The intestinal lining also acts as a barrier to toxins and microbes. To do this effectively, large numbers of cells in our intestinal lining die each day and are replaced by new cells, created from a small population of stem cells.

Trained as a developmental biologist, Helen is fascinated by this process.

'Blood and skin renew constantly, but not quite at the rate of the intestinal lining' Helen says, 'So, if you're interested in developmental pathways, as I am, then the intestine is a great organ to study.'

Helen says a healthy intestinal lining maintains exactly the right balance between dying and renewing cells. Too many new cells can lead to tumours and bowel cancer, a leading cause of cancer deaths in Australia.

Too few new cells can denude the intestinal lining and cause painful inflammation and ulcerations, which can happen after infections or cancer treatment, such as chemotherapy or radiotherapy.

It can also happen in the 10 per cent of premature babies who get necrotising entrocolitis, often treated by removing large sections of the bowel, leaving some of them unable to draw enough nutrition from ingested food.

Bowel cancer patients who undergo surgery and accident victims with injured intestines face similar problems, since intestinal tissue dies quickly if the blood supply is interrupted.

Helen is trying to identify the pathways that control intestinal stem cell production in the hope of identifying targets for future treatments.

'All cells reproduce by dividing, and many traditional cancer treatments affect all dividing cells, which is why you get side effects,' Helen says. 'They are far too broad'

When intestinal stem cells divide, some 'differentiate' and become intestinal lining cells and some remain undifferentiated 'daughter' stem cells, from which the next generation of lining cells and daughter stem cells will come.

'If too many undifferentiated stem cells are made,' Helen says, 'you may end up with a tumour, and if you don't get enough, you're going to lose your intestinal lining eventually'

Helen says her team has identified several molecules involved in this process, which, if removed, results in all the stem cells differentiating without producing daughter stem cells.

Perhaps more remarkably, she says her research may help identify cancer stem cells that produce cancerous tumours and daughter cells for future tumours.

If found, they would give developers of future bowel cancer treatments clear targets to ensure tumours never return, especially the most aggressive kind.

Helen is collaborating with doctors led by Associate Professor Paul McMurrick from Cabrini Hospital to see if particular markers correlate to particular tumours, allowing them to be graded according to severity. 

Her laboratory team is growing organoid or "mini gut" cultures from tissue from bowel tumours and using this culture method to test the response of different individual tumours to drugs.

'We're hoping that our research will eventually allow a surgeon to remove a tumour and test it against a panel of drugs that will indicate the best treatment.'

Helen is also trying to understand if a patient's stem cells could repair an intestine by either stimulating them to regenerate more efficiently in the body or by taking tissue samples to increase their number in culture before returning them.

'This is not pie-in-the-sky stuff because we have quite good candidates. We haven't got to the point of showing repair, but we know the effects of some of the growth factors in cultures.'