Cancer ‘stem cells’ are something of a hot topic in research circles at the moment. Despite decades of research and clinical trials, advanced cancers, especially once they spread in the body, are notoriously difficult to control or eradicate. Professor Mel Greaves at the Institute of Cancer Research argues this month in Nature that the genetic makeup of cancer stem cells may help explain how patients become resistant to drugs.
When designing new drugs, cancer stem cells have been widely regarded as the ‘bull’s-eye’ in the target. Recent research by Prof Greaves’ team into the most common form of childhood cancer, acute lymphoblastic leukaemia (ALL), reveals that the crucial stem cells that drive the cancer have, within individual patients, many different sets of mutations.
This work, funded by 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 ‘natural selection’ in the body.
“This Darwinian perspective has important implications for leukaemia and cancer therapy,” says Professor Greaves. “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.
Professor Greaves has in fact shown 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.
While thankfully over 90% of children now survive childhood ALL, the long term survival rates for children who relapse remain tragically much lower. The ‘Darwinian’ model of cancer development offers a convincing explanation of why children might relapse. It seems clear that developing a deeper knowledge of how leukaemia stem cells operate and how some may evade treatment is vital to making sure that all children survive in the future.
Henry Winter - Science Communications Team