A new research by Australian scientists published recently in the journal Nature Communications have revealed that cancer cells that lie ‘snoozing’ in the skeleton can be awakened – or left to sleep on – by changes in the bone that surrounds them. This research by researchers at the Garvan Institute of Medical Research is first of its kind and makes uses of state-of-the-art microscopy techniques to watch cancer cells sleep within living bone over a period of months. This study is significant as it suggest ways of exploring new possibilities for treating metastatic cancer in bone.
In many cancers the cancer cells can spread from the original tumour site into bone. Once spread, they settle there and often remain inactive for months or even years. Eventually, when some of these cells wake up, they begin dividing and form secondary cancers in bone dramatically worsening the outcome for cancer patients.
Professor Peter Croucher, the study’s lead investigator and Head of Garvan’s Bone Biology Division said that once a cancer spreads to bone, it becomes quite difficult to treat. Hence, it is important to understand what wakes up the cancer cells from its slumber is it a change in the environment or it is a signal within the cells.
The research team made use of a groundbreaking technique called intravital two-photon microscopy, the researchers observed what happens to the sleeping cancer cells in the tibia -the main bone in the long part of the leg of a living mouse. They introduced cells from multiple myeloma (a cancer of blood cells that arises in bone) into the mouse, and watched as a small number of the cells lodged in the tibia and drifted into slumber. For detection these cells were marked with a fluorescent dye that was lost rapidly from dividing (wakeful) cells.
Dr. Tri Phan, who co-led the study, remarked that since long bone like a tibia was studied instead of commonly studied skull bones, the researchers could watch the same sleeping cancer cells, in the same bone, in the same mouse, over a long period of time. That is something that hasn’t been tried before. Since, the same set of cells over a prolonged period were studied, it gave vital clues about what reactivates some of them said Prof Croucher. He added that it was observed that the cells that woke up did so at different times. In fact, some cells that woke then went back to sleep again.
The fact that despite coming from the same cancer line the myeloma cells behaves differently led the researchers to the clue that it is a signal from outside the cells that is controlling when they wake. Dr. Michelle McDonald, a bone biologist on the research team, opined in this study, it has been found that bone’s dynamic process of building up and breaking down can send signals to cancer cells to sleep on or to wake. Cells known as ‘osteoblasts’ help build new bone, while ‘osteoclast’ cells break down bone. It has been observed that myeloma cells are usually kept asleep by close association with a layer of osteoblast-like cells, called bone-lining cells, in the endosteum (an internal surface within bone). The bone-lining cells are inactive and provide a quiet environment in which myeloma cells sleep undisturbed.
The myeloma cells can be woken up by activating osteoclasts, which break down bone tissue thereby changing the environment in which the cancer cells sleep. It is a known fact that bone remodeling is an ongoing process happening in all of us – so a myeloma cell could be woken in an essentially random fashion when the local environment of the cancer cells is remodeled by osteoclasts.
Prof Croucher remarked that since it is now understood that the cancer cells are woken by changes in the surrounding bone, two treatment approaches for treating bone metastasis hold promise. The first is that the breakdown of bone by osteoclasts could be inhibited by drugs, so as to keep cancer cells in long-term hibernation. The second is to do the opposite – to wake the sleeping cells by activating osteoclasts and driving the breakdown of bone. Most cancer therapies target active, dividing cells, so it will make the dormant cells more susceptible to therapies and any residual disease could be eradicated.