Cancer stem cells (CSC) are a strange beast. They’re familiar to what we know about stem cells, yet vastly alien in their behaviour and contribution to cancer. For all intents and purposes they are just like normal stem cells, a feature that gifts them with biological characteristics detrimental to our fight against the disease.
They are thought to be responsible for tumours recurring following ‘successful’ treatment and for the development of secondary cancers, so it’s no surprise that finding out how to stop CSC is a key priority for cancer research – particularly at Breakthrough’s Research Unit in Manchester.
What makes something ‘stem-like’?
Stem cells are the versatile ‘shape shifters’ of the cellular world, capable of becoming any cell type in the body. They play an incredibly important role in early development of an embryo when precisely timed chemical signals potentiate stem cells to become specific types of cell. They are also essential throughout life for the generation of new cells and repair of damaged organs. CSC harness ‘stem-like’ characteristics to be able to become any cell type found in a tumour. It is for this reason that they are considered to be the type of tumour cells responsible for seeding and initiating the development of new tumours.
The ‘stem-like’ properties of these cells also allow them to be naturally resistant to chemotherapeutic agents. Although not a great deal is known about why these cells are so resistant to treatment, there are features of both normal and cancer stem cells which offer some explanation. For example, the surface of a stem cell is dotted with pores, called transporters, which act as pumps to flush drugs back out of the cell before they can do any damage. These cells are also particularly hardy and are capable of surviving damage to their DNA which you would normally expect to kill them. It is likely that these survivors linger on following treatment and could be responsible for cancers coming back.
Professor Michael Lisanti
It’s crucial then that science explores this strange world of ‘stemness’ and finds weaknesses in CSC which can be used as the basis for new types of treatment. In a recent study, led by Professor Michael Lisanti’s team at Breakthrough’s Research Unit in Manchester, researchers have described a new way to potentially eradicate CSC by attacking a feature which makes them stand out from the crowd.
Targeting the cells engine
The problem with studying CSC is that there isn’t a great deal of them in a tumour sample and so trying to identify specific druggable targets can be difficult. To overcome this problem the researchers used a special technique to grow breast cancer cells in mammospheres. These mammospheres – or ‘clumps’ of cells – are more likely to harbour CSC and make studying the stem-like characteristics much easier.
When the team analysed the molecular features of mammospheres they stumbled across something quite surprising – many of the cellular chemicals involved in generating power for the cell were at levels not seen in normal cells or in other, non-stem like, cancer cells.
This is extremely interesting because it seems that a unique feature of CSC is directly linked to the cells’ engines, known as mitochondria, and an engine breakdown is one sure way to bring a cell to a halt. The researchers tested this hypothesis by treating breast cancer cells with chemicals which block the mitochondria from producing the power needed for CSC to survive. The cells were grown as before and the team noticed a reduction in the number of mammospheres – a result suggesting the treatment successfully targeting CSC.
MCT inhibitors - a future treatment?
The drug they used is from a class of compounds called ‘MCT inhibitors’ (a drug that blocks a protein called MCT) and promisingly, some of these are already in clinical trials. The pharmaceutical company AstraZeneca and the charity Cancer Research UK are running an early stage trial to test a MCT inhibitor for many different cancer types.
Lab research, such as Breakthrough’s Manchester study, provides evidence that these drugs could treat cancer but this is the first time that one of these compounds is being tested in humans.
Although research has shown that the protein MCT and the cells mitochondria play an important role in the growth and development of cancer in the lab, it’s still not clear exactly how we can target them with therapeutics. Mitochondria are the power houses of all our cells so messing around with how they function could have detrimental effects to a patient.
What the results from Breakthrough’s team in Manchester do show us is that by exploring the characteristics which make CSC stand out, we can identify specific targets for treatment. Hopefully, these will one day emerge as novel ways to eradicate CSC and prevent cancer recurrence and progression to secondary disease.
Dr Matthew Lam is Breakthrough Breast Cancer's Senior Research Officer