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Stem cells in a bowel adenoma

Researchers are homing in on the ‘stem cells’ that seem to drive some forms of cancer (Image courtesy of Science/AAAS)

Biology has its share of contentious issues, and the existence of cancer ‘stem cells’ – treatment-resistant cells at the heart of a tumour – is certainly controversial.

We’ve written before about these enigmatic cells, but they’ve made the headlines again this week, so we wanted to re-visit the issue.

The headlines appeared thanks to the publication of three exciting research papers in top international journals, Science and Nature, which showed, in beautiful, fluorescent detail, the development of tumours from what look to be some form of ‘stem-like’ cell.

Let’s have a look at what the researchers did, and what it means.

So what’s the buzz about?

We now know that the cells in a tumour aren’t all carbon copies of each other, but display a striking array of characteristics. Some cells show signs of specialisation (also called differentiation), while others do not. And some cells are actively dividing while others appear to just sit there quietly.

This diversity, also known as heterogeneity, was first observed in the nineteenth century and its importance has been the source of scientific debate and controversy ever since.

The cancer stem cell hypothesis takes this idea and runs with it. It suggests that some cells in the solid tumour are definitely more equal than others. Most cells in a tumour, it argues, lie idle – providing little more than bulk. The cells that really matter are the cancer stem cells –the elusive and exclusive ‘inner circle’ capable of dividing and replenishing the tumour, the queen bee of the hive.

The queen is dead, long live the queen!

Continuing with the beehive analogy, the appeal of the cancer stem cell idea suddenly comes into sharp focus; just as killing the queen bee leads to the demise of the hive, destroying the cancer stem cells, should, in theory, stop the tumour from renewing itself. And it’s an idea that has drawn a dedicated following among some of the scientific community. It’s been argued that treatments sometimes fail because they only kill the bulk cancer cells (the equivalent of worker bees) not the cancer stem cell.

Kill the workers and the queen leads the hive to recovery. Kill the queen – or stem cells in a tumour – and it’s game over.

But scientists are a sceptical species. Even the best ideas need to be proved before they can be accepted, and the cancer stem cell hypothesis is no different. Proving that stem cells play an important part in tumour growth has been fraught with difficulties – finding ways to isolate them is technically challenging, so sceptics have argued that the tests used are littered with inadequacy.

And to complicate the matter even further, context is everything in biology – what holds true in the breast or pancreas won’t necessarily occur in, say, the prostate. Proving the cancer stem cell theory won’t be a matter of a single, definitive experiment, but rather the steady accrual of pieces of a complex puzzle.

So would the real cancer stem cell please stand up?

Lineage tracing

‘Lineage tracing’ experiments involve tagging individual cells with a fluorescent tag and following their fates
(Image courtesy Science/AAAS)

At this very moment, the puzzle is still incomplete. But three important pieces were put in place this week.

Three research groups each took a different cancer type and asked the same question: were the majority of cells in a tumour descended from a small number of ancestors (as the cancer stem cell theory would predict) or were they a mixed bag?

In other words, is there a queen bee in residence?

Although each group worked on a different tumour type (cancers of the brain, bowel and skin), they all made use of an ingenious biological technique called lineage tracing. Individual cells are given a coloured tag that they pass on to their daughter. This means that a cell’s ancestry can be determined simply by looking at their colour.

Reporting in Nature, a team of Belgian researchers led by Dr Cedric Blanpain provided compelling evidence that cancer stem cells play an important role in skin cancer. His group found that, in mice, cells in benign skin tumours (called papillomas) all originated from a select few cells. In the image below illustrates this: the cells in red are descended from a single red-tagged stem cell:

Cancer stem cells

In this skin tumour, the cells labelled red all arose from a single stem cell (Credit: G. Driessens)

Meanwhile in the Netherlands, Professor Hans Clevers’s team focused on the cells in the bowel. His team labelled single intestinal cells either red, yellow, blue or green.

When adenomas (benign tumours that can progress into bowel cancer) were allowed to develop, they tended to be a single colour, implying that they all arose from a single cell.

Cancer stem cells in the bowel

In this image, the green cells are bowel stem cells (courtesy H. Snippert)

Both these studies were done in benign tumours, but what about malignant tumours – these are the ones that we tend to think of as ‘cancer’, as they have the potential to spread. In the US, a team led by Professor Luis Parada also used lineage tracing to show that most of the cells in a type of brain tumour called glioblastoma were descendents of a select few cells (presumably cancer stem cells).

He also went further, first showing that chemotherapy removed the bulk of the tumour but left these cancer stem cells untouched. And then, in an elegant series of experiments, his team found that cells from tumours that came back after treatment were all descendents of these cancer stem cells. Finally, they found that combining chemotherapy with genetic trickery to remove these cells led to collapse of the entire tumour.

Put together, these papers are the strongest evidence yet that the existence of a solid tumour depends on a small group of cancer cells with ‘stem cell-like’ properties. And more importantly, it seems that any treatment for tumours that have spread will only be able to cure people if it attacks these cancer stem cells.

So if we zap cancer stem cells into oblivion, we can all go home?

Unfortunately, things are never that simple. All three studies were performed in mice so the obvious next step is to show that these cells are equally important in human cancer. Next, we have the potential problem of collateral damage to deal with. There’s the risk that treatments against cancer stem cells would also damage the normal, healthy tissue stem cells that help replenish cells following injury or normal wear and tear. If that were indeed the case, the consequences could be disastrous.

And there might be another challenge. In the hive, workers react quickly to the death of the queen by replacing her with a new one. And there is some evidence to suggest that could happen in the tumour due to a phenomenon known as ‘cell plasticity’ that allows normal tumour cells to turn into cancer stem cells, should the situation call for it.

But scientists all over the world, including our own are rising to the challenge. They’re finding the subtle differences that distinguish normal tissue stem cells from cancer stem cells. This will allow them to design treatments targeted specifically at the faults, which would leave healthy tissue stem cells unharmed. And they’re also asking whether a stem cell’s natural habitat, or its microenvironment, might be modified to make it a more hostile place for cancer stem cells.

Only time will tell whether this research really does represent a ‘paradigm shift’, as the BBC wrote this week, or whether we’re in for more twists and turns in the stem cell debate over the coming months.

What’s certain though is that such laboratory research – such as the work we’re funding up and down the country – is crucial if we’re to unravel the mystery of the queen bee in the hive: the cancer stem cell.

References

  • Driessens, G., Beck, B., Caauwe, A., Simons, B.D. & Blanpain, C. (2012). Defining the mode of tumour growth by clonal analysis, Nature, DOI: 10.1038/nature11344
  • Chen, J., Li, Y., Yu, T.S., McKay, R.M., Burns, D.K., Kernie, S.G. & Parada, L.F. (2012). A restricted cell population propagates glioblastoma growth after chemotherapy, Nature, DOI: 10.1038/nature11287
  • Schepers, A.G., Snippert, H.J., Stange, D.E., van den Born, M., van Es, J.H., van de Wetering, M. & Clevers, H. Lineage Tracing Reveals Lgr5+ Stem Cell Activity in Mouse Intestinal Adenomas, Science, DOI: 10.1126/science.1224676

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