Cancer’s dark Darwinian secret revealed

Despite decades of research and clinical trials, advanced cancers, especially once they spread in the body, are notoriously difficult to control or eradicate. Now new research into leukaemia has shed light on what might lie behind this stubborn intransigence to therapy and, remarkably, it may be as fundamental as evolution itself

Recent research from the Human Genome Project into the most common form of childhood cancer, acute lymphoblastic leukaemia (ALL), has revealed that the crucial stem cells that propagate the cancer have, within individual patients, variegated and diverse mutation profiles. 

In the study published in the journal Nature, Professor Mel Greaves at The Institute of Cancer Research, London and Professor Tariq Enver at the University of Oxford, showed that distinctive and often complex sets of mutations appear to drive each individual cancer.

The findings could be highly significant in influencing how cancer drugs are designed in the future. Cancer stem cells have been widely regarded as the ‘bull’s-eye’ in the target for therapy. This new research, funded by the blood cancer charity Leukaemia & Lymphoma Research, suggests that there is no single bull’s-eye but rather multiple targets that are diverse and constantly shifting. It vividly confirms that, as long suspected, cancer clones evolve in a Darwinian fashion by genetic variation and ‘natural selection’ in the body.

“This Darwinian perspective has important implications for leukaemia and cancer therapy,” says Professor Greaves, who led the study. “Our research may help explain why advanced cancers remain so difficult to eradicate. A massive investment is being made in developing new drugs for advanced cancer that target the tumours’ specific genetic mutations as potential ‘Achilles heels’. Whilst some of the new drugs show considerable promise, it is important to recognise that these genetic mutations are constantly evolving, which has the potential to create lethal resistance.”

A cancer stem cell is created when a single healthy stem cell becomes genetically mutated. These mutated stem cells then go on to clone multiple copies of themselves, driving and sustaining the cancer. It had been assumed that leukaemia developed in a ‘linear model’, with leukaemia stem cells acquiring additional genetic mutations with successive divisions. Variations in the combinations of genetic abnormalities found within different cancer stem cells were thought to represent earlier versions of the cancer stem cell in its development.

The new study in fact showed that in the very early stages of the disease the original cancer stem cell produces distinct ‘sub-clones’ of itself. Each of these sub-clones contains different combinations of genetic mutations and will go on to develop further sub-clones independently of each other, like branches. While some sub-clones will be destroyed by drugs, other branches may be resistant to treatment and become dominant, driving the cancer forward.

Co-author of the report, Professor Tariq Enver, now of the UCL Cancer Institute, who led the research at the Weatherall Institute of Molecular Medicine, University of Oxford, says: “Our research suggests that drugs are more likely to be effective for longer if they target properties shared by all cancer stem cells in each patient, so this is an important area for further investigation. It also endorses the view that early intervention or, where possible, prevention, is likely to be more effective.”

While it is still assumed that the cancer comes from one blood stem cell ‘going wrong’, this new study proves the theory that instead of developing ‘in a straight line’, the original cancer stem cell goes onto produce different cells with different genetic abnormalities, which develop independently of each other, like branches.

The practical implications of this model on choosing treatment options for relapsed leukaemia in particular are potentially enormous. Thankfully survival rates for ALL, which is diagnosed in around 450 children a year, have improved significantly thanks to research and improvements in treatments. From being a virtual death sentence 50 years ago, now 90% of patients survive – however long term survival rates for children who relapse are tragically much lower. The ‘Darwinian’ model of cancer development offers a convincing explanation of why children might relapse.

Cancer cells have sub-clones in them that make them vulnerable to some drugs – genetic ‘markers’ that allow them to be targeted. These recent findings offer a highly convincing explanation of why some children relapse early from treatment. The theory goes that while the majority of the ‘branches’ of cancer cells have been targeted by traditional drugs, some cancer stem cells remain with sub-clonal variations which can evade the drugs. A regime of new drugs will be needed to treat these cells. Conversely, if a child relapses after a long period of remission, it can be reasonably assumed by doctors that retreating with the original drugs could be successful.

Dr David Grant, Scientific Director at Leukaemia & Lymphoma Research, says: “This recent study has huge practical implications and it will be important to assess, as is likely, if this model of cancer stem cell development holds true for other types of leukaemia and cancer in general.”

It is certainly suspected that the model of cancer stem cell development in childhood ALL is be similar in a range of other types of leukaemia and cancers. Establishing whether this is the case is an obvious avenue for further for investigation, but it could be harder to demonstrate. Leukaemia cells tend to contain a relatively small number of abnormalities, typically between two and eight. Other cancers can contain hundreds of abnormalities, making their development much harder to study.

While establishing a model of how leukaemia stem cells proliferate represents a huge step forward, work still needs to be done to find a definitive explanation of how cancer stem cells are ‘triggered’ into causing leukaemia.

In 1988, Professor Greaves first pioneered the idea that the trigger for childhood leukaemia is an abnormal response to infection. He has since identified infection as one of the causes of ALL in children.

The idea is that our immune systems have not properly adapted to modern life. Improved hygiene and small family size mean that infants are not exposed to infection in the way they would have been years ago. Therefore, the immune system, which relies on constant infections to build up resistance to disease, is not ‘hard-wired properly and misfires later in life’.

In January 2008 Professor Greaves and his colleague Professor Enver confirmed for the first time, in research published in Science, the existence of childhood ALL stem cells. This groundbreaking research was also funded by Leukaemia & Lymphoma Research.

“Our study compared the blood cells of identical twins Olivia, who was being treated for leukaemia, and Isabella who is healthy,” says Professor Greaves. “We found the same genetically abnormal pre-leukaemic stem cells in the blood of both twins. From this we were able to confirm theories that childhood ALL starts in the womb. We are now investigating why and how these pre-leukaemic stem cells are converted into full-blown leukaemia in some children and not others.”

Confirming the existence of cancer stem cells in both twins added weight to the theory that infection sets off the leukaemia, since only one of them had developed leukaemia. “There must be some sort of trigger activated in some children and not others. The evidence suggests that the “second trigger” is related to timing and an unusual response to infection. If we complete our understanding of how the immune system triggers leukaemia to develop from stem cells, I think it will be possible to prevent childhood ALL altogether,“ says Professor Greaves.

The discovery of cancer stem cells has greatly added to our understanding of how some cancers spread and consequently has given the drug industry a valuable insight into how they can be treated. This latest study is just one of many in recent years which has added to our understanding of the mechanisms of the development of leukaemia. ‘Basic’ laboratory research has allowed huge leaps forward in survival rates, particularly for childhood ALL, which is now over 90%. Breakthroughs such as this are important in designing new drugs for the 10% of children who tragically do not currently respond to treatment.