Different colours show different environments in the bone marrow. Credit: Edwin Hawkins and Delfim Duarte, Imperial College London
Most cancer treatments come from scientists studying molecules inside cancer cells.
But in recent years, researchers have begun turning their microscopes on the cells and molecules surrounding tumours instead.
This world around cancer cells is known as the tumour microenvironment.
It’s made up of healthy tissues, such as blood vessels and immune cells, which can be hijacked to help tumours grow, spread and dodge treatment.
And researchers have become increasingly interested in this ‘good-neighbourhood-turned-bad’.
Their goal is to understand how these tissues can be brought back under control to treat cancer more effectively, and stop drug resistance emerging.
And now, a group of scientists led by Dr Cristina Lo Celso at Imperial College London, supported by Cancer Research UK and Bloodwise, has made a fascinating discovery about the neighbourhood where a type of leukaemia develops: the bone marrow.
In a study published this week in the journal Nature, the team reveal for the first time what happens inside the bone marrow as the disease develops.
And by studying this neighbourhood during treatment, the findings could open up a new way to tackle drug resistance.
Dem bones dem bones
Bones might not look very dynamic from the outside, but inside they are a hive of activity.
As well as being the scaffolding that gives us shape and protects our vital organs, bones also make red and white blood cells in the bone marrow (the soft part inside the bone).
Blood cells have a very short shelf life – on average the bone marrow churns out around 500 billion new blood cells every day to keep us in tip top working order.
And it’s this endless production of new blood cells that can lead to blood cancer. Just a single genetic mistake in one of the dividing cells could be the first step in the development of leukaemia.
Fast-growing, or acute types of leukaemia, need treating quickly with intensive chemotherapy. But drug resistance is a problem – if some of the leukaemia cells survive, the disease comes back.
“We set out to find out more about how these leukaemia cells become drug resistant,” says Lo Celso. “If we understand what signals, or special compartments in the bone marrow the leukaemia cells are hijacking, we would have a strong starting point to develop better treatments to combat these resistant cancer cells.”
Uncovering the mysteries of marrow
Although leukaemia cells are born in the bone marrow, they leave for the bloodstream and circulate like normal blood cells. But, according to Lo Celso, this has been a problem for studying this type of cancer.
“Most of the cancer samples we study are blood samples taken from patients, so we really have very little understanding of what’s happening in the bone marrow when the disease begins, or as drug resistance develops.”
To get a clearer picture of the way leukaemia cells behave in the bone marrow, the researchers studied mice with T-cell acute lymphoblastic leukaemia. They used sophisticated microscopes and computers to track individual cancer cells inside the bone marrow as leukaemia develops.
And as shown in the image below, the yellow leukaemia cells can be clearly seen in among the structures in the bone marrow, coloured purple and blue.
“The first thing we saw surprised us. There was no particular part of the bone marrow the leukaemia cells prefer to settle in, for example near bone or next to blood vessels. Instead, they move around at a fairly steady speed, spreading out in the marrow,” says Lo Celso.
No shelter from the chemotherapy storm
But what happened during treatment came as a real turn up for the books.
“When we gave the mice chemotherapy, we expected to see the small population of leukaemia cells that become resistant take shelter in particular areas of the bone marrow,” says Lo Celso.
Based on previous experiments, they thought resistant leukaemia cells would need to settle in a small neighbourhood to survive the onslaught.
“That’s not what we saw at all,” Lo Celso explains. “The resistant leukaemia cells stayed spread out, and actually moved faster during treatment. They weren’t retreating to pockets of safety, like we thought they would.”
The chemotherapy did halt the growth of leukaemia temporarily, because the resistant cells weren’t dividing as much as untreated cells. But they soon started growing again, creating a new army of hardier leukaemia cells that weren’t susceptible to chemotherapy.
“Interestingly, the most intensive combination of chemotherapy we used made the resistant cells move about even faster,” Lo Celso says.
And this discovery could lead to changes in treatment.
A different approach for new treatments
The team’s findings reveal important details about the way cancer cells behave in the bone marrow that might open the door to developing new ways to tackle leukaemia.
“Our original goal was to identify leukaemia’s hiding place to develop drugs that flush out the cancer cells, and stop them becoming resistant to chemotherapy,” Lo Celso says. “But there is no ‘hiding place’ to target.”
If we can figure out why the osteoblasts are dying, we might also be able to develop treatments to stop this happening
– Dr Cristina Lo Celso
“However, our work suggests that leukaemia cells could depend on moving about and touching lots of cells within the bone marrow to survive. And that opens the potential to look for ways to stop or slow their travels, or block them from contacting other cells,” she adds.
The researchers also found that the bone marrow itself changes as leukaemia develops, which could severely affect how it functions.
“While we were observing the bone marrow, we noticed that soon after the mice developed leukaemia, specialised bone marrow cells called osteoblasts disappeared,” Lo Celso says. “These osteoblasts are crucial to the bone marrow being able to produce blood cells normally.”
If bone marrow can’t produce enough red and white blood cells, it can leave leukaemia patients dangerously ill – either through insufficient red blood cells to carry oxygen to organs (anaemia) or vulnerable to life-threatening infections due to a shortfall in immune cells.
“If we can figure out why the osteoblasts are dying,” says Lo Celso, “we might also be able to develop treatments to stop this happening. And this could protect patients from one of the most serious consequences of leukaemia by keeping their red and white blood cell numbers up.”
As leukaemia’s nosey neighbour, Lo Celso and her team may have taken the first steps towards new treatments that prevent acute forms of leukaemia coming back after chemotherapy. And their findings could one day protect patients from the life-threatening effects of their cancer.
Following on from their studies of mice, Lo Celso’s team have already confirmed that leukaemia cells behave the same way in patients, which reinforces their research as a promising avenue to pursue.
They also want to find out if the same dodgy dealings are happening in other types of leukaemia.
Research like this is vital in understanding how cancer evolves to escape therapy, shining a light on ways to cut off the disease’s escape, and ultimately helping more people survive.