This image shows an adult mouse mammary gland duct. Lrg6 positive cells are shown in green, luminal cells in blue and basal cells in purple. Courtesy of Fabio Pucci/ The Francis Crick Institute
Cancers start when faulty genes cause cells to grow uncontrollably.
But these cancer-triggering cells do more than just get a tumour up and running – they also continually fuel its growth.
And these cells that a cancer stems from – helpfully named cancer stem cells – are a crucial focus for scientists looking to understand cancer.
That’s because, frustratingly, these cells tend to be able to shrug off treatments such as chemotherapy and radiotherapy.
Revealing the identities of these cells is therefore important in our battle against cancer. So in order to lift the veil on these elusive cells, scientists are retracing the steps a tumour takes as it develops, following it right back to where the cellular journey begins.
And a handful of stunning images released this week reveal how researchers are beginning to piece together this journey for some types of breast cancer.
Published in the journal Nature Cell Biology, scientists from the Francis Crick Institute – part-funded by Cancer Research UK – identified a particular type of cell that can trigger breast cancer in mice, and keep those tumours growing.
Importantly, the images also reveal that these cells could be a good target for treatment.
A glowing report
Different cells have their own unique identities, and these can be given away by the various molecular ‘tags’ that they brandish on their surface.
But it’s one particular tag that helped illuminate these breast tumours.
The molecule is called Lgr6, and it’s found on stem cells in various parts of the body, including the taste buds, lungs and skin.
“Lgr6 is a well-known stem cell marker in certain tissues,” says co-lead author Dr Fabio Pucci, from the Francis Crick Institute.
“We’re trying to understand the connection between stem cell populations in the breast and the origin of some breast cancers, so we wondered whether this protein might also mark stem cells in the breast.”
To get to the bottom of this, the researchers used a red fluorescent molecule which sticks to cells that carry the Lgr6 molecule, and tracked the fate of these cells in mice.
In the mammary gland, which produces milk in mammals, they found that these particular cells contained genetic ‘signatures’ that were characteristic of a type of immature cell called a progenitor cell.“Whereas stem cells can give rise to lots of different types of cell, progenitor cells can only become one type of cell,” Pucci explains.
In fact, the team discovered that there were two groups of progenitor cell in the mammary gland that were marked by Lgr6. And it was these cells that gave rise to the two types of cell that make up the mammary gland tissue: basal cells and luminal cells.
The researchers also found that cells carrying Lgr6 go on to form the basket-like network of milk-carrying tubes that develop during pregnancy, which you can see in the striking microscope images to the right and below.
The blue shows the milk-producing luminal cells, explains lead researcher Dr Leander Blaas from the Karolinska Institute in Sweden, whereas the green highlights a type of cell called a myoepithelial cell. These cells, Blaas says, squeeze tiny milk-filled sacs together in order to push the milk through the ducts towards the nipples.
Of mice and women
So these Lgr6 carrying cells help healthy mammary gland tissue develop. But what about breast cancer?
Next, the team looked for Lgr6 in more than 500 human breast cancer samples and found it was present in roughly half of the tumours.
And it was here that they also spotted a link between the levels of Lgr6 and patient outcome – the less Lrg6 that was present in the samples, the longer patients were free from signs of disease after treatment.
But it was in their final series of experiments in mice that the possible involvement of Lgr6 cells in breast cancer became clearer.
Here the team switched off genes inside the Lgr6 cells that are frequently lost in cancer, including the well-known BRCA1 and p53 genes. Sure enough, these animals developed breast cancers, indicating that the progenitor cells can act as tumour initiating cells.
On closer inspection, the team found that the mice developed a particular type of cancer: luminal breast cancer.
But this runs counter to what might have been expected.
In people, faults in the BRCA1 and p53 genes tend to cause a different type of breast tumour called a basal tumour.
“No matter what genetic fault we made, we always got luminal-like tumours,” Pucci says. “This tells us that perhaps, in some cases, the cell of origin is more important in determining the type of cancer that arises than the specific genetic faults.”
And when the researchers looked at mice that were predisposed to breast cancer, not only were Lgr6 cells found to contribute to early tumour growth, they also played a role in maintaining the fully-developed tumours. And removing these cells slowed the growth of the tumours.
An obvious target
The researchers conclude that Lgr6 cells can help breast tumours start. But what does that mean for patients with the disease?
“If this work is confirmed in further studies, it will open the doors for new treatment approaches,” says Pucci.
If this work is confirmed in further studies, it will open the doors for new treatment approaches.
– Dr Fabio Pucci, Francis Crick Institute
“Because Lrg6 is found on the surface of cells, it will be a very easy target for developing potential treatments – it’s much easier to target something that’s on the outside of a cell than the inside.”
Encouragingly, Pucci says, removing the Lrg6 cells in mice didn’t seem to affect their health, so it may well be a good target for drugs.
But the journey from studying a tumour’s origins to finding new ways to treat it is a long one. What happens in mice may not reflect what happens in people, so it’s too early to say whether targeting Lgr6 could represent an effective way to treat breast cancer.
But every scientific journey has a beginning, and it’s only further research that will help define what stems from this discovery.
Blaas, L. et al. 2016. Lrg6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours. Nature Cell Biology. doi:10.1038/ncb3434