Tumours that have spread around the body are trickier to treat successfully.
So finding molecules that help cancers progress, and developing ways to disable them, is crucial in tackling advanced tumours.
LOX is one such molecule.
Short for ‘lysyl oxidase,’ its main job is to help form a supportive scaffold around cells called the extracellular matrix, which gives tissues their structure.
That’s a hugely important role in the body. But LOX also has a dark side.
We’ve revealed more about how LOX is involved in promoting growth signals in cancer cells
– Professor Caroline Springer
Research has suggested it can rejig the extracellular matrix in such a way that not only encourages tumours to grow, but also helps them spread.
Now, an important new study from our scientists may have found a way to block this troublesome molecule, which could be turned into a treatment to help tackle cancer.
“We’ve revealed more about how LOX is involved in promoting growth signals in cancer cells,” says Professor Caroline Springer from The Institute of Cancer Research, one of the study’s lead researchers.
Working closely with a group headed by Professor Richard Marais at the Cancer Research UK Manchester Institute, the scientists have also developed an experimental drug which can block tumour growth and spread in mice. And they hope to take this drug on to clinical trials.
A faulty transmission
Much of scientists’ knowledge about LOX focuses on how it affects the area surrounding cells. It causes chains of molecules like collagen to join up and stick together, creating a mesh that gives tissues structure and strength.
But in cancer, this process can also create the ideal environment for wandering tumour cells from other parts of the body to settle in. These breakaway cells can then go on to form secondary tumours, or metastases, which is the major cause of death from cancer.
Studies have hinted that there is more to the story though, and that alongside its effects on the outside of cells, LOX also meddles with what’s going on inside cancer cells.
That’s why the researchers behind the latest study, published in the journal Nature Communications, were keen to unpick its role even further, and examine the effects of tampering with it in cancer.
The team first lowered the amount of LOX produced by cells in the lab, and then examined the effects this had on the cells. They did this by looking at the levels of molecules on the surface of the cells, which ‘catch’ chemical signals from the outside and relay these messages inside, ultimately telling the cell what to do.
The scientists discovered that LOX affected the levels of a molecule called epidermal growth factor receptor, or EGFR, at the surface of cells. EGFR tells cells to grow and is frequently faulty in cancer. The team’s results suggest that LOX could be causing it to be held on the surface, meaning one of the cell’s ‘grow’ signals is essentially stuck on.
“We showed that, through a complex of molecules, LOX is involved in maintaining EGFR at the cell surface,” says Springer.
“Here, EGFR is then able to promote signalling in cancer cells.”
Breaking the chain
The next step was to try and develop molecules that can inhibit LOX on the surface of cells.
“LOX is involved in promoting tumour growth and metastasis, which is why we wanted to find inhibitors that could help block these processes,” says Springer.
One LOX drug already exists, called BAPN, which is commonly used in lab studies. But Springer explains that it has a number of problematic characteristics that make it unsuitable for development into a drug for people.
We wanted to find inhibitors that could help block [tumour growth and metastasis]
– Professor Caroline Springer
“It’s tiny and non-selective,” she says, meaning it messes with other molecules as well as LOX. “It also has to be used in enormous concentrations in order to be active.”
So they set about designing a better version.
After 7 years of hard work, the team finally came up with something that’s not only capable of blocking LOX, but is also 16 times more effective at doing so than BAPN.
They then gave this inhibitor to mice that were predisposed to develop breast cancer that spreads to the lungs, and found that it not only slowed the growth of primary tumours, but also reduced the amount that spread to the lungs. Encouragingly, the scientists didn’t observe any side effects in the mice.
And when they looked closely at the tumours of the treated animals, they found that the cells didn’t have EGFR stuck to their surface.
Broadening the horizon
So now the team has a promising experimental drug on their hands, does that mean it’s ready for testing out in people? Not quite.
“This is the first reported inhibitor since BAPN that has the potential to go forward into the clinic, but it might not be developed into a drug,” says Springer.
“We developed it as a panel of different inhibitors that we’re testing out in preclinical studies so that we can find the best candidate for further clinical development.
“We’ll then select the best two later this year to take into clinical trials.”
And although this particular study focused on breast cancer, Springer says that the implications of this research could stretch further.
“Work by us and others have shown that LOX is also involved in pancreatic and bowel cancer,” she adds, raising the possibility that blocking LOX might have potential in several types of cancer.
While it’s too early to say whether that will be the case, this early research is exciting nonetheless.
And it could potentially lead to treatments that help stop cancer from spreading, which patients urgently need.
Tang, H. et al. (2017). Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface. Nature Communications. DOI: 10.1038/NCOMMS14909