Like the astronomical explosion that kickstarted the universe, bowel cancer has a "Big Bang" moment which determines how it will grow, according to new research from Cancer Research UK and Wellcome Trust-funded scientists.
Researchers at The Institute of Cancer Research, London, Fondazione Human Technopole in Milan and Chalmers University of Technology in Sweden have found that the "Big Bang" moment for bowel cancer is created by cancer cells successfully hiding themselves from the immune system – a process called immune escape.
During this process, bowel cancer cells disrupt genes which allow the cancer to be detected by the immune system. After the point of immune escape, the scientists observed that very limited changes occurred in how the cancer presented itself to the immune system.
This research provides a potential way that doctors could identify people with bowel cancer who are more likely to respond to immunotherapy, including vaccines for bowel cancer, which are designed to help the immune system recognise and destroy cancer cells.
Professor of Genomics and Evolution and Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, London, Professor Trevor Graham, said:
"Some bowel cancers are 'born to be bad.' How they interact with the immune system is set early on.
"Immunotherapy and bowel cancer vaccines hold enormous promise for treating the disease. Our research suggests that a bowel cancer's relationship with the immune system doesn't change very much as it grows. If we can target that relationship early on, treatment should have a stronger chance of success.
"As bowel cancer treatment becomes increasingly personalised, understanding how tumours evolve and change matters even more than it did before. Like the explosion which set the course of the universe, bowel cancer's Big Bang gives us the biggest clues of what its future holds and how we might change that future."
Bowel cancer is the fourth most common cancer in the UK with around 44,100 new cases in the UK every year, roughly 120 every day. Around 15% of bowel cancers are known to respond well to immunotherapy, with the remainder less likely to respond to this type of treatment.
Several therapeutic bowel cancer vaccines are currently in clinical trials. Designed to train the immune system to prevent bowel cancer from coming back after initial treatment, they recognise and destroy newly emerging bowel cancer cells.
Study lead author Eszter Lakatos, a mathematical biologist at Chalmers University of Technology and the University of Gothenburg, Sweden, said:
"Our research group has investigated and found answers to how cancer cells render themselves invisible to the immune system. Our hope is that these insights will eventually lead to more targeted, effective and early treatments, in addition to surgery."
In the study, the scientists analysed the organisation of immune and cancer cells in bowel cancers from 29 people. They generated full DNA and RNA sequences and looked at how closely the DNA was wound around proteins in the chromosomes (known as epigenetics).
The scientists found that cancer cells can escape the immune system through epigenetic changes which alter how DNA is "read" to make RNA, the instructions used to make proteins.
In cancer, those alterations affect how many neoantigens - "red flag" proteins that attract immune cells – appear on the surface of the cancer cell. Fewer neoantigens make it harder for the immune system to recognise and destroy the cancer.
Scientists believe that combining immunotherapy with epigenome-modifying drugs could make immunotherapy work better for bowel cancer patients, by making the cancer make more neoantigens which the immune system can target. Further studies are needed to test this idea, before patient clinical trials could start.
Director of Research at Cancer Research UK, Dr Catherine Elliott, said:
"To beat bowel cancer for everyone, we need to understand what happens at the very earliest stages of the disease. No matter how different bowel cancer tumours can look, one defining moment at the start makes a big difference to how the cancer grows.
"Bowel cancer has an insidious ability to resist treatment. Immunotherapy is starting to work well for patients, but it doesn't work for everyone. This research helps us understand why, as well as giving us new insights to make immunotherapy work better for bowel cancer."
Research Lead for Discovery Research at the Wellcome Trust, Tom Collins, said:
"Through tracing the earliest stages of bowel cancer, the research team has shed valuable new light on a mechanism that could lead to more targeted, effective and early treatments.
"This is a powerful example of discovery science. Research at this molecular level has provided a deeper understanding of how bowel cancer develops, which could lead to the improved health outcomes for patients in the long-term."
The paper, titled "Epigenetically driven and early immune evasion in colorectal cancer evolution", was published today (5 November) in Nature Genetics*.
