No man is an island – we exist together with other people in families, communities and societies. The same is true of cancer cells – they need a host of non-cancerous cells, collectively known as the tumour microenvironment, to help them grow and develop.
In the latest of our Expert Opinion interviews we talk with Professor Fran Balkwill, who argues that treating the tumour and its microenvironment together represents an exciting frontier for cancer treatment.
Cancer Research UK: Can you explain what the tumour microenvironment is?
Fran Balkwill: Most people know that cancer is caused by cells that have developed faults in their DNA. But that’s only half the story. At least half of any tumour will be lots of other cells. Like any normal tissue or organ, tumours need the help of other cells to survive.
For example, fibroblasts provide structural support, while endothelial cells form blood vessels that deliver oxygen and nutrients and remove waste. Also, all tissues have immune cells patrolling in and out of them, which in normal circumstances act as the body’s police force, fighting off disease and infection. Together, these cells make up the tumour microenvironment; it’s a complex system that supports and nourishes the tumour.
Cancer Research UK: Is this a new area of cancer research?
Fran Balkwill: It actually goes back to the 1870s when the great German pathologist Rudolf Virchow first noticed that there were white blood cells in tumours. So it’s been known for nearly as long as we’ve had microscopes to look down. But for a long time, people thought that these cells were fighting the cancer. But now we know that cancers hijack these normal tissue support systems into something that helps them grow and spread.
Cancer Research UK: Why is studying the tumour microenvironment so important?
Fran Balkwill: I believe that to have a really effective long term treatment for cancer, you need to do more than target the malignant cells. The tumour microenvironment makes up about half of all the tumour and we know that there are cells in there that are supporting the tumour to grow. So logically, by stopping that, you’re making it more difficult for the tumour to grow. We also know that there are other cells in there that should be capable of stopping the tumour growing but they don’t do it because they’ve been corrupted or blocked.
The exciting targeted treatments we have now – whether they’re tyrosine kinase inhibitors, PARP inhibitors, BRAF inhibitors, Herceptin – they all target the cancer cells themselves; but over time, these cells evolve and the treatment may stop working. Cancer’s a moving target, but I think combining the great specificity and high response rate of the targeted treatments with something that targets the tumour microenvironment will give a longer lasting response. So targeting the tumour microenvironment has the potential to be a very credible weapon in our fight against cancer, working alongside the other treatments. It won’t work on its own, but I believe it will be an accepted part of the way you treat cancer.
Cancer Research UK: What has been your most significant contribution to this field so far?
Fran Balkwill: I was only a small cog in a large machine but I highlighted the link between inflammation and cancer. Inflammation is an important part of our body’s defence against infection and injury. It usually only happens for a brief time and is tightly controlled – the process does a very good job and then switches off. However, in certain diseases, inflammation does not switch off properly and becomes chronic. In the tumour microenvironment you can find many characteristics of this chronic inflammation. I showed that certain cytokines – these are molecules involved in inflammation – have pro-tumour action. Cancer cells generate these complex inflammatory cytokine networks to control their microenvironment.
So cancer and inflammation are closely connected and there are five pieces of evidence to support this. Firstly, some chronic inflammatory diseases can increase the risk of cancer. For example, people with pancreatitis have a higher risk of developing pancreatic cancer. Second, we know that long-term use of certain anti-inflammatory drugs (such as aspirin) can reduce the risk of some cancers types. Third, we find many of the cell-types (such as macrophages) that are important in inflammation are present in large numbers in the tumour microenvironment. We also know, from experiments in model systems, that deleting or blocking these inflammatory molecules or cells has an anti-cancer effect and finally, when we manipulate healthy cells in the lab and turn them into cancer cells, they start producing inflammatory cytokines.
Cancer Research UK: What is your lab focusing on now?
Fran Balkwill: We’re especially interested in the cytokines tumour necrosis factor (TNF) and interleukin-6 (IL-6). We try and understand how they work and then we try and understand how inhibitors of them might work in cancer. We know that inhibitors of IL-6 and TNF have fantastic effects in some patients with major inflammatory diseases such as rheumatoid arthritis; also we know they’re safe to give to people who are very ill so we’re trying to understand if they have any action in cancer, and if so, what?
We don’t expect any of them to work on their own, but we do think they might work alongside other treatments.
We concentrate on high grade serous ovarian cancer, but what we discover I think is going to be much more broadly significant. If we do have a success in this, it will be much more significant to a whole range of different cancers and different stages of cancer as well.
Cancer Research UK: What do you most enjoy about your job?
Fran Balkwill: It’s never boring! I love being part of a big international community, travelling and collaborating with colleagues across the world. And seeing my people develop as scientists; I think that’s great as well. You make a little impact by making a lot of impact on other people who go on to do great things in cancer research.
Interview conducted by Safia Danovi