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Here’s a guest post from Dr Jo Peak, one of the Science Information team at Cancer Research UK, about an interesting paper published recently.

Why is it so difficult to ‘cure cancer’?

We often describe people who have been successfully treated for cancer as being ‘in remission’ – but not ‘cured’. This is because, sadly, cancer can come back. These relapses seem to be down to a few stray cancer cells that are left behind after treatment, which start to multiply again. This can occur many years after the initial treatment.

At the moment, doctors remain cautious in telling people that they are truly ‘cured’ of cancer, as it’s virtually impossible to be 100 per cent sure every single cancer cell has been killed off.

In recent years, researchers have begun to solve this difficult problem by showing that not all cancer cells are equal – preventing cancer’s return seems to be a case of targeting the right ones. Now researchers led by Dr Pandolfi at Harvard Medical School have discovered another piece in the puzzle.

Many cancers, particularly blood cancers such as leukaemia, are believed to contain a very small group of ‘cancer-initiating cells’ (CICs) – also known as ‘cancer stem cells’. As their name suggests, these are the conductors that orchestrate the growth and maintenance of the cancer.

Although drugs are effective at killing the bulk of the cancer cells, these CICs tend to be highly resistant to treatment and can survive in the body – only to restart the tumour’s growth at a later date.

Scientists at Cancer Research UK and across the world are looking at ways to specifically target these CICs and completely eradicate cancer from the body. This field has been spurred onwards by a report in Nature this week revealing how leukaemia-initiating cells persist in the body and drive chronic myeloid leukaemia (CML). The authors have also used this knowledge to come up with a possible way to kill off this critical group of troublesome cancer cells.

What are ‘cancer-initiating cells’?

The idea of CICs has been around since the 1960s. At the time, scientists studying cancers of the blood system (leukaemias and lymphomas) made the initial observation that only a very small percentage of cancer cell samples are able to re-grow either in the lab or when transferred into mouse models.

In 1997, Dr Dominique Bonnet, who now runs her own research group at our London Research Institute, made a real breakthrough in this field when she actually isolated a group of leukaemia initiating cells from patients with acute myeloid leukaemia.

These CICs have also been called ‘cancer stem cells’, as they share many properties with the normal stem cells that keep our bodies ticking over. Stem cells can both re-generate themselves, and – crucially – develop into many other types of cell. A key unanswered question is whether these CICs actually arise from mutations in normal stem cells, or whether the CICs are ‘normal’ cells that have just become a bit ‘stem-cell-like’.

But the real problem with CICs lies in the fact that they are highly resistant to treatment. Like normal stem cells, they contain molecular pumps on their surface that keep out toxic cancer drugs. Furthermore, many conventional cancer treatments exploit the fact that the bulk of the cells in a tumour are actively dividing and kill cells by blocking cell division. But CICs exist in a dormant or ‘quiescent’ state where they are not actively dividing, making them harder to target with most conventional treatments.

So this leads to a situation whereby the cells actually driving cancer growth are the ones that are most likely to be left behind after treatment.

So how can we kill CICs?

In their Nature paper, Dr Pandolfi and his team show that CICs in leukaemia rely on a molecule called promyelocytic leukaemia protein (PML) in order to keep their stem cell-like properties and drive the development of chronic myeloid leukaemia (CML).

To discover this, the researchers took normal blood stem cells and turned them into CICs by adding a gene that causes CML (an oncogene called BCR-ABL). They then removed the PML protein from these cells and found that they couldn’t cause leukaemia when they were transplanted into mice.

Further investigation revealed that losing PML activated another molecule called mTOR, which pushed the CICs from their dormant resting state into an actively dividing state. This meant that the pool of stem cells got used up, as they were not regenerating new CICs.

Fortunately, PML has already been studied in great detail by scientists as it plays a role in another type of leukaemia – acute promyelocytic leukaemia (APL). Through this work – including recent research funded by Cancer Research UK - we know that arsenic is an effective treatment for leukaemia because it targets PML for destruction.

Armed with this knowledge, the authors of this study used arsenic trioxide to block PML activity in CICs and reawaken them from their dormant state. They then tested whether these rapidly dividing CICs were more sensitive to chemotherapy. This approach proved to have dramatic effects.

CICs pre-treated with arsenic and chemotherapy were no longer able to cause leukaemia when transplanted into mice. In fact, the researchers observed increased cancer cell killing leading to a complete cure in more than half the animals they tested.

The findings of this study represent a major step forward in how we think about treating leukaemia and many other cancers driven by CICs. This work shows that if we can find effective ways to reawaken CICs from their resting state and force them to divide, we can make them much more sensitive to cancer treatments.

This may seem to go against the grain, as we are normally trying to stop cancer cells dividing. But to kill CICs, this appears to be the best way forward. Using this approach, we would hope to improve the chance of eliminating these key ringleaders from the body, and move a step closer towards achieving a real ‘cure’ for people with cancer.

Jo

Picture courtesy of the Cancer Research UK London Research Institute EM Unit

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