to the tibia of a mouse
Image courtesy of the Garvan
Institute of Medical Research
Cancer cells that lie dormant in the bone can be “woken up” by changes in their surroundings, according to researchers.
The group used microscopy techniques to study multiple myeloma (MM) cells that lay “sleeping” in mouse bones.
The experiment revealed that dormant cells can be reactivated when bone tissue is broken down around them, suggesting new possibilities for
treating metastatic cancers in bone.
“Once a cancer spreads to bone, it becomes notoriously difficult to treat,” said study author Peter Croucher, PhD, of the Garvan Institute of Medical Research in Sydney, New South Wales, Australia.
“So it’s important to establish exactly what wakes those cells in bone. Is it some signal within the cells themselves, or is it a change in their environment?”
The researchers set out to discover which scenario is correct and reported their findings in Nature Communications.
Using a technique called intravital 2-photon microscopy, the team tracked the fate of dormant MM cells in the tibia of living mice.
They introduced MM cells into the mice and watched as a small number of the cells lodged in the tibia and “went to sleep.” These cells could be detected because they contained a fluorescent dye that was quickly lost from dividing cells.
“Because we were looking at a long bone like a tibia, we could watch the same sleeping cancer cells, in the same bone, in the same mouse, over a long period of time, and this is something that hasn’t been done before,” said Tri Giang Phan, PhD, of the Garvan Institute of Medical Research.
Dr Croucher said that studying the same set of cells over a period of months revealed vital clues about what caused them to reactivate.
“Because we’ve done it this way, we can show that there are a great many dormant cells, yet only some of them get woken up, and those that do wake, wake at different times,” he noted.
“We even saw some cells that woke then went back to sleep again. The fact that these myeloma cells behave so differently, despite coming from the same cancer cell line, gave us our first clue that it is a signal from outside the cells that is controlling when they wake.”
Explaining the phenomenon
The researchers’ next challenge was to determine the precise nature of the “wake-up call” from bone.
“[W]e’ve shown that bone’s dynamic process of building up and breaking down can send signals to cancer cells to stay sleeping or to wake,” said Michelle McDonald, PhD, of the Garvan Institute of Medical Research.
“We were able to show that myeloma cells are usually kept asleep by close association with a layer of osteoblast-like cells, called bone-lining cells, in the endosteum. The bone-lining cells are essentially inactive, so we can think of them as providing a quiet environment in which myeloma cells sleep undisturbed.”
“Crucially, we can wake those myeloma cells by activating osteoclasts, which break down bone tissue. We think the osteoclasts are physically changing the local environment of the cancer cells and waking them up in the process, as if they were literally throwing them out of bed.”
“We know that bone remodeling is going on in all of us. So a myeloma cell could be woken in an essentially random fashion, by having its local environment remodeled by osteoclasts. Essentially, a cancer cell could be woken by being in the wrong place at the wrong time.”
Implications for treatment
So what do these findings mean for treating secondary cancers in bone?
“Now we can see that the cancer cells are woken by changes in the surrounding bone, we can think in a whole new way about treating bone metastasis,” Dr Croucher said. “And there are 2 treatment approaches in particular that have promise.”
“The first is that we could inhibit the breakdown of bone by osteoclasts so as to keep cancer cells in long-term hibernation. In fact, there are already drugs that can do this, such as bisphosphonates, and there’s already evidence that these drugs do improve survival in breast cancer patients.”
“The other, more radical, option is to do the opposite—to wake the sleeping cells by activating osteoclasts and driving the breakdown of bone. Most cancer treatments target active, dividing cells. So waking the sleeping cells should make them susceptible to those therapies and, ultimately, could eradicate any residual disease.”
