This Forum marks the formation of the Australasian Chapter of the International Metastasis Research Society – OzMRS. OzMRS grew out of the strong local interest in metastasis research, which became obvious when the 14th International Biennial Congress of the Metastasis Research Society (MRS) was held in Brisbane in 2012. OzMRS was formally established in 2013 and became an affiliated organisation of the Clinical Oncology Society of Australia (COSA). Articles in this Forum have been contributed by OzMRS members and illustrate the comprehensive approaches being taken in Australia to understand the molecular and cellular basis of metastasis and thereby provide better outcomes for those afflicted with metastatic cancer.
The development of metastatic disease is a devastating event for cancer sufferers since, in many patients, it is likely to be the cause of their death. Primary cancers can usually be treated successfully with localised therapies including surgery and radiotherapy, but neither of these treatments is generally curable in the setting of distant metastases, unless a very limited number of secondary lesions are present. Given the fact that it is metastatic disease that leads to the demise of most patients with solid cancers, there is a major world-wide research effort to identify the genes, proteins and processes that regulate metastasis, to understand the contribution of host cells, including the major role of the immune system in metastasis, and to find targeted therapies against either the tumour cells or against tumour-promoting host cells.
The process of metastasis is complex, involving many genes and signalling pathways, both intrinsic to the tumour cells and those that influence the surrounding (host) tissues. Specific metastasis promoting and metastasis suppressing genes have been identified in tumour cells, where they regulate metastasis but have little impact on primary tumour growth, as reviewed by Roesley et al.1 Therapies based on targeting these genes are being developed, since they are the initial drivers of metastatic disease. If we can block these genes we may indeed remove or reduce the risk of metastasis altogether.
However, many normal host cell lineages are also vital for the successful metastasis of a tumour, and provide additional opportunities for therapy. The circulatory systems, including the vasculature and the lymphatics, are essential to the growth of tumours and in addition, provide the avenues of escape for primary tumour cells and their carriage to distant tissues where secondary tumours can develop. Therapies are being developed to target both of these circulatory systems, with some anti-angiogenic therapies already in standard clinical use. Reviews of the contributions of these two circulatory systems are provided by Karnezis and Ramin for lymphatics and by Mellick et al for vasculature.2,3
As our preclinical models of metastatic disease improve to more closely reflect events that occur in patients, we have come to recognise the major contribution of various immune cell lineages to metastasis. While the initial response of the immune system is to attack the tumour cells, factors secreted by tumours subvert some immune cell lineages into tumour promoting cells, as described in the article by Edgington-Mitchell and Parker.4 Hence the concept of targeting the immune system to avoid tumour progression to metastatic disease is gaining considerable momentum, with several anti-immune therapies in clinical trials.
Over the past few years, attention has been focused on the presence and significance of tumour cells in circulation. Technological advances have allowed researchers to detect very low numbers of these circulating tumour cells in blood, allowing their prognostic significance to be assessed, as reviewed by McInnes and Saunders.5 The idea of analysing blood as a ‘liquid biopsy’ also extends to detection of cell-free DNA derived from the tumour cells and to exosomes secreted both from tumour cells and from host cells in response to the presence of the tumour. As reviewed by Wen et al,6 exosomes are small microvesicles that contain proteins, lipids and RNA that can be transferred between cells. Evidence exists to show that tumour-derived exosomes can modulate the host to promote tumour growth and establish a more favourable metastatic site before the tumour cells even arrive. Initial investigations into the prognostic value of these small particles that can be isolated from the circulation are underway.
There is increasing realisation that many primary tumours have metastasised prior to diagnosis. Hence, our focus needs to remain on effective therapies for established metastases, although it will also be important to prevent metastasis during therapy and from established metastatic lesions. It is remarkable that secondary disease may not become apparent for many years following successful treatment of the primary tumour. This latent metastasis is known as dormancy, whereby a solitary tumour cell or a micrometastasis can remain viable, but unable to expand into a clinically detectable lesion. It is proposed that eventually, a few of these dormant cells break free from this restraint, through mechanisms not at all well understood and hard to study experimentally. The concept of dormancy and its clinical relevance is reviewed by Chakrabarti and Anderson.7
The altered metabolism that occurs in cancer cells has become a major research focus in recent years and several genes involved in metabolism are now recognised to act as oncogenes. The analysis of metabolic pathways and genes that are altered in tumours offers a new therapeutic opportunity, as well as a means of monitoring tumour progression and response to therapy in patients. Pouliot and Denoyer review the key findings in this area and the use of positron emission tomography to image the changes in metabolism that occur in tumours during therapy.8
One of the challenges in treating metastatic cancer is the influence of the microenvironment in which the secondary tumour grows. It is well known that specific types of cancer metastasise preferentially to some tissues and not others. For example, breast, prostate and lung cancers, and melanomas, are more likely to home to bone than other types of cancer. In addition, some cancers metastasise to the brain, where the blood-brain barrier strongly influences our ability to treat these tumours. This concept of site-specific metastasis has led to the development of specific therapies for secondary tumours at different sites and also indicates very strongly the profound influence of the tumour microenvironment on the growth of metastases. Hossain and Dunstan discuss the unique microenvironment of the bone and how this allows for some specific therapy options, although they remain mainly palliative at this stage.9
A more general review of strategies to treat metastases at different sites by targeting the tumour microenvironment is presented by Quah et al,10 bringing examples from clinical trials of a number of tumour types, including prostate, breast, lung and colorectal carcinomas, and melanomas both in the skin and eye. A number of therapies targeting stromal fibroblasts, infiltrating immune cells, blood vessels, signalling molecules, extracellular matrix and tissue oxygen levels have been tested, as described in their article.
Another major challenge for successful therapy of progressive cancer is the heterogeneity that develops between the primary and secondary tumours. It is likely that subpopulations of the primary tumour are able to metastasise and their response to therapy will be different to that of the primary tumour. Kutasovic et al discuss the evidence for heterogeneity in clinical samples and the consequences of this heterogeneity for therapy, using breast cancer as an example.11 It is now apparent that tumour heterogeneity is a major cause of the intrinsic or acquired resistance to therapy.
The pace of metastasis research has increased in recent years, offering the potential of new therapies to combat progressive disease. Our better understanding of the molecular mechanisms and more clinically relevant animal models of metastatic disease will allow the development of therapies that provide a significant benefit for patients for whom current therapies provide only palliative relief.