Metastasis of cancer cells to bone is common in patients suffering from advanced stages of cancers that originate in distant organs such as breast, prostate, and lungs. Once in the skeleton, cancer cells acquire “bony” characteristics that enable them to influence and disrupt the function of bone cells such as osteoclasts – the bone cells that are responsible for removal of old bone. This culminates in the development of a set of skeletal complications including excessive bone damage and bone pain.
Cancer-related bone damage is not only caused by bone metastasis but also by chemotherapy. There is an expectation that the risk of bone damage among cancer patients would increase, as more cancer patients survive longer.
Existing drug treatments such as Bisphosphonates and Denosumab are effective in reducing cancer-related bone damage by killing the osteoclasts. However, other aspects of the disease such as homing of cancer cells to bone and the disruptive impact of cancer cells on the function of bone and immune cells are inadequately managed. Thus, there is an urgent need to develop new drugs for the treatment of secondary cancer in bone.
Why we shouldn’t ignore the role of inflammation in the skeleton
Inflammation plays a critical role in cancer and bone remodelling, the process by which old bone is removed and replaced by new bone. Previous studies carried out in our laboratories and others have revealed that NFκB, a key modulator of inflammation, is implicated in the metastasis of breast cancer cells to bone and its inhibition reduced breast cancer-related bone damage. These findings led us to hypothesise that disrupting the function of individual components of NFκB signalling in breast cancer and/or bone cells may be of value in reducing both breast cancer bone metastasis and related bone damage.
Of all known components of the NFκB pathway, a protein called TRAF2 has recently been identified as one of the genes that cause breast cancer. TRAF2 has been shown to regulate osteoclast function and its inhibition reduces the ability of osteoclasts to form, survive and cause bone damage. Encouraged by these findings, we decided to investigate if TRAF2 is implicated in the metastasis of breast cancer cells to bone and whether it contributes to the disruptive behaviour of “bony” breast cancer cells in the skeleton.
Our research in a newly published study in Scientific Reports reveals there are two sides to this story. We showed that over-expressing TRAF2 in human breast cancer cells enhanced their growth when injected into the mammary fat pads of mice, but failed to cause these naive cells to metastasise to bone. Undeterred by this, we went on to hypothesise that TRAF2 plays a role in the behaviour of breast cancer cells once in the skeleton.
In confirmation of this hypothesis, we first noted that a number of the TRAF family of proteins – including TRAF2 – were highly expressed in human and mouse breast cancer cells obtained from the bones of mice suffering from breast cancer. In order to understand what TRAF2 is doing in these bony breast cancer cells, we over-expressed TRAF2 in these cells to study their ability to home and grow in bone, and to cause bone damage in mice. We have found that mice injected with TRAF2 over-expressing cells experienced increased tumour growth, higher osteoclast number, and excessive bone damage when compared to mice injected with control breast cancer cells.
To identify which inflammatory mediators are produced when TRAF2 expression is enhanced in cancer, we carried out a detailed proteomics analysis of the tumour derived factors produced by bony breast cancer cells over-expressing TRAF2. This shows that TRAF2 activation is associated with excessive production of cytokines, chemokines as well as a myriad of pro-inflammatory mediators that are known to enhance the differentiation, movement, function, and survival of osteoclasts. When combined with previous studies, our recent results suggest that inhibitors of TRAF2 may be of value in the management of both primary and secondary breast cancer in bone.
The challenge of therapeutic targeting of TRAFs
Members of the TRAF superfamily of proteins have diverse functions in inflammation and the immune system. As a proof of principle, our recent study is exciting and represents an important piece of the puzzle. However, designing drugs that selectively target and inhibit the activity of individual TRAFs in breast cancer cells in the skeleton without affecting the function of other cells such as immune cells will be an onerous task.
The other challenge is whether TRAF2 inhibitors will also target and inhibit the functions of other members of the TRAF family – a family comprised of 7 proteins some of which share many structural features. Besides this, there are many signalling pathways that are activated by TRAF2 – other than NFκB – that we need to identify and better understand.
The good news is that research on the role of inflammation in the regulation of metastasis is growing among cancer researchers. At our laboratory at the University of Sheffield, we are currently designing and testing a new class of tumour-selective TRAF inhibitors. Such studies will open new opportunities to develop TRAF inhibitors – alone or in combination with chemotherapy – for the treatment of metastatic cancer.
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