Tracking down bowel cancer stem cells

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

Stem cells are a hot topic in cancer. In recent years we’ve seen the rise of the “cancer stem cell” concept – the idea that many cancers are caused by a small group of immortal stem cells. These produce ‘bulk tumour cells’, which can be killed off by treatments such as chemotherapy, but the stem cells themselves are resistant to treatment.

The cancer stem cell theory provides a neat explanation of why cancers can come back after many years, but the idea is controversial. Some researchers think that all cancers boil down to stem cells, while others maintain that only a proportion of cancers are fuelled by these cells.

There’s certainly good evidence for the involvement of cancer stem cells in leukaemia, and scientists have suggested that stem cells drive many other types of cancer, including breast, skin and prostate.

US scientists writing recently in the journal Nature used new techniques to show that melanoma skin cancer – a disease that had previously been thought to be driven by stem cells – defied the theory, ramping up the controversy.

But this week’s Nature carries a report from Cancer Research UK scientists in Scotland and Cardiff, working with researchers in the Netherlands, showing that stem cells are at the root of bowel cancer.

A knockout blow
Dr Owen Sansom from the Beatson Institute for Cancer Research and his colleagues carried out a neat experiment to show that bowel stem cells could ‘go rogue’ and fuel cancers.

Due to everyday wear and tear, the cells that line our bowels are constantly being replaced. New cells are produced from stem cells deep within cavities (crypts) in the bowel wall, in a complex biological ‘production line’. This process is tightly controlled – too few new cells would lead to the bowel lining breaking down. But over-production of cells can lead to cancer.

In their experiments, Sansom and his team used genetic engineering techniques to ‘knock out’ the activity of a crucial gene called APC in healthy bowel stem cells in the small bowel of mice. They discovered that tumours developed within a few days, which aggressively spread within a few weeks.

Next, the scientists knocked out APC in normal bowel lining cells, and found that tumours also developed, but much less readily or frequently than those from the stem cells.

The results suggest that the stem cells are much more likely to give rise to cancer that the lining cells. The scientists also found that the stem cell-derived cancers produced ‘bulk’ cancer cells similar to bowel lining cells, supporting the classic cancer stem cell concept.

So we now know that stem cells are likely to be the fuel for bowel cancers – at least in mice. But does it hold true for humans too?

Similarities and differences
Obviously, it’s virtually impossible to do genetic engineering experiments directly in humans. But we do know that the mouse system the team was using is a very good model for the development of human bowel cancer.

There’s one key difference though. Experiments with mice have shown that their bowel cells only need one or two major gene faults to push them down the cancer path, whereas human bowel cells need several more. But these results suggest that stem cells are ‘on the brink’, and need only a relatively small genetic push – whether that’s one fault or several – compared with other cells in the bowel.

More experiments need to be done before we know for sure whether stem cells play a vital role in human bowel cancer. For now, these results are a promising step in the right direction – and a confirmation that the stem cell theory may well hold true for at least one type of cancer.

If we can understand more about the molecular pathways that control cancer, we can start to design new, more effective ways to prevent and treat the disease.

Click on the player below to hear Dr Sansom talking about his work in a short audio clip:

Link to download (1.5Mb, 3min10)

Kat