Cambridge scientists have shown that when tumours first emerge, interactions with healthy cells in the underlying supportive tissue determine their ability to survive, grow, and progress to advanced stages of disease.
The study, carried out in mice and further validated using human tissue, may explain why some tiny, newly-formed tumours disappear, while others manage to survive and eventually grow into cancer.
Tumours arise when our DNA accumulates errors, or mutations, causing the cells to grow faster and ignore signals that would otherwise instruct damaged cells to die before they can cause harm. However, these same mutations can also accumulate in the tissues of healthy people during ageing without developing into cancer.
To examine why this should be the case, scientists at the University of Cambridge have been studying what additional factors influence tumour formation at the very early stages and what determines whether they persist and develop into cancer.
Previous collaborative work by the team had shown that when a newly-formed microscopic tumour first emerges in a tissue, it can be removed by other mutant cells surrounding it, which compete for space within the tissue. But this does not always happen. Scientists have puzzled for some time over why some of these so-called 'incipient tumours' manage to outwit the body's defences and flourish, creating the conditions for advanced disease to develop.
To answer this question, a team led by scientists at the Cambridge Stem Cell Institute and the Department of Physiology, Development and Neuroscience, University of Cambridge, modelled early stages of cancer in the upper part of the mouse digestive tract.
The researchers replicated key features of human disease by exposing mice to a chemical found in tobacco smoke, a known cancer risk factor. This causes mutations in the cells lining the oesophagus (gullet), leading to the development of microscopic tumours, most of which disappear naturally as described above – but some persist.
The team then tracked these nascent tumours over time, from the point when they were made up of just over a handful of altered cells (around 10 cells) through to later stages of disease. They analysed the tumours and surrounding cells using high‑resolution confocal microscopy and a range of tools, including single‑cell RNA sequencing and genetic cell tracking, to understand what each cell was doing. In addition, the team grew three-dimensional tissue in the lab, allowing them to model the interactions between the tumour cells and surrounding tissue.
In findings published today in Nature, the researchers found that at these early stages, the tumour sends a 'distress signal' to nearby fibroblasts – supportive 'first-aid' cells in the underlying tissue. This communication triggers a response that closely resembles wound healing. The fibroblasts behave as though the tissue has been damaged, producing a fibrotic scaffold around the tumour cells. This creates a supportive micro‑environment – a 'pre-cancerous niche' – that shelters the tumour from being cleared and helps it persist and grow.
Remarkably, the researchers found that this fibrotic scaffold alone was enough to give healthy, non-mutant cells tumour-like properties, even in the absence of cancer-causing mutations. This suggests that beyond genetic alterations, early tumours are shaped by how healthy cells in the underlying tissue respond, with lasting consequences for disease progression.
When the researchers examined tissue from early-stage oesophageal cancers in humans, they found similar clusters of tumour cells sending stress signals, as well as the same fibrotic scaffolding seen in the mouse models, demonstrating that this mechanism is also relevant in people.
Dr Greta Skrupskelyte from the Cambridge Stem Cell Institute, one of the lead authors, said: "A decade ago it was assumed that it is the mutated cells themselves that determine whether or not a cancer arises. Our findings show that the way healthy tissue responds to the emergence of early tumours also plays a crucial role in whether disease develops."
When the team blocked the communication between the tumour cells and the underlying tissue, they found that the pre-cancerous niche did not form efficiently, and far fewer early tumours survived.
Dr Maria Alcolea, also from the Cambridge Stem Cell Institute, said: "Understanding the mechanisms that allow these newly-formed microscopic tumours to persist and develop into cancer opens up new possibilities for preventing the disease before it takes hold.
"If we can find a way to block tumour cells from communicating with surrounding tissue, we may have a new way to stop cancer in its tracks."
The researchers say the findings could also, in future, help improve early diagnosis of oesophageal cancer, a disease that is often caught at a late stage, when treatment options are more limited.
Dr Skrupskelyte added: "Although the clinical aspects of our work are at a very early stage, it has given us some biomarkers – red flags – that could help identify cancer much earlier. If validated, it could help us catch oesophageal cancer at a much earlier stage, when it is far easier to treat."
The research was mainly funded by Worldwide Cancer Research, the Wellcome Trust, The Royal Society, the Medical Research Council and the Isaac Newton Trust.
