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  • The importance of the microenvironment for cancer developmen

    2019-05-10

    The importance of the microenvironment for cancer development and progression is now widely recognised, but it is worth reminding ourselves that this is a relatively young area of research. Anyone searching PubMed today using the terms “” will find over 22,000 scientific publications, with around 3000 new contributions in both 2014 and 2015. However, going back 10 years to 2004 there were only 364 papers published fitting these terms, hence keen researchers would have the capacity to read them all. Changing the search terms to “”, results in 3400 papers with around 420 new contributions per year for 2014 and 2015, compared with 93 papers a decade earlier. Inclusion of the word limits the number of hits further, but in all cases the trend is towards ever increasing numbers of annual scientific publications that include studies of the microenvironment, indicating an active research area in rapid growth. The renewed interest in the microenvironment in cancer may in part come as a result of the realisation that the human SAR405 project (completed 2003) did not deliver as much insight into cancer development as was hoped. Subsequent efforts to sequence cancer cell genomes and identify driver mutations were published from 2006 onwards, with the data on new cancer types regularly emerging, most recently in breast cancer . However, it was clear that the translation of this wealth of new data into knowledge and increased understanding of cancer biology, ultimately identifying new therapeutic targets, was going to take time, and that new gene-based cancer therapies were not just round the corner . The concerted effort of the Cancer Genome Atlas (TGCA) program (started in 2006) has yielded a wealth of information relating to cancer-subtypes and identified numerous mutations, but processing and interpreting its 20 petabytes of data, including 10 million mutations, is a mammoth task . As the complexities of the cancer cell genome and its regulation became evident, scientists also started to consider how different cell types work together, and Hannahan and Weinberg predicted this to be of great importance in their original “” paper published in 2000 . In this they stated: This statement has turned out to be astonishingly accurate, reflecting the general view of the cancer biologists of today that understanding, and ultimately successfully treating, cancer, depends on unravelling how a multitude of cell types co-operate. How the components of the microenvironment contribute to tumour development was subsequently mapped on to the hallmarks of cancer in the 2012 paper from Hannahan and Coussens “”, which describes the contribution of a large number of both cellular and molecular components to tumour progression . At the same time as huge efforts were made to characterise individual cancer cells, there was increasing realisation that tumours are heterogeneous, both in terms of the tumour cells but also in their stromal component , and that the presence of different clones underpins the development of resistance to therapy. This heterogeneity introduces further layers of complexity in our quest to understand cancer, and highlights that analysis of individual components of a tumour and characterisation of single cells may not be fruitful. For researchers with an interest in bone metastasis, the role of the microenvironment has always been an integral part of their thinking. As described by Rob Coleman in this issue (see page 90), bone-targeted therapies were shown to be effective in advanced disease in the early 1980s, initiating research into the connection between bone and tumour growth. This ultimately generated the hypothesis of the vicious cycle proposed by Mundy and colleagues, where tumour-bone interactions result in accelerated tumour growth and associated cancer-induced bone disease . Initially, the focus of bone metastasis research was the osteoclast and its key role in cancer-induced bone disease. However, it soon became clear that even highly effective inhibition of bone resorption was insufficient to prevent tumour progression in bone, suggesting that other cell types and numerous molecular/cellular drivers were involved. As described by Le Pape and colleagues in this issue (see page 93), the role of the osteoclast in cancer-induced bone disease is now well characterised. However, the role of the osteoclast in the early stages of tumour cell colonization of bone is less clear, with recent studies using multi-photon microscopy to demonstrate that zoledronic acid treatment does not inhibit tumour cell homing to bone in mice . The osteoclast may therefore have a role in the subsequent steps of stimulating the growth of disseminated tumour cells to form colonies.