Chemotherapy becomes less effective because healthy cells push cancer cells to grow more slowly, according to the findings of two studies from University College London (UCL) and Yale University.
Bowel cancer kills over 900,000 people a year and is the second highest cause of cancer mortality worldwide. In the UK, it accounts for 10% of all cancer deaths.
In the first study, UCL researchers used single-cell analysis technologies to measure how 1,107 mini-tumours derived from mice responded to changes in both their genes and their environment.
Analysis revealed that bowel cancer cells are fast-growing or slow-growing, and that healthy cells can push bowel cancer cells towards the slow-growing state. Because chemotherapies target fast-growing cells, these slow-growing cancer cells are more likely to be resistant to treatment.
Dr Chris Tape, a senior author of the studies from UCL Cancer Institute, said: “Recent research has shown that bowel cancer patients with more healthy cells in their tumour, including cells called fibroblasts that are involved in wound healing, often have a poor prognosis. But what we didn’t know until now was why this is the case.”
Slow growing state protects cells from chemotherapy
In the second study, the team sought to confirm their findings in human cells, using over 2,500 mini-tumours grown from donated tissue from bowel cancer patients who had undergone surgery.
Results showed that factors such as patient age and the specific mutations a tumour carried did not affect how the cancer responded to chemotherapy. The key factor was how fast-growing the cancer was. Healthy fibroblast cells could slow down cancer growth in some patients, completely protecting the cancer from chemotherapy.
Dr Maria Ramos Zapatero, UCL Cancer Institute, said: “The slow-growing state that we observed in these bowel cancers is very unusual and normally only found during foetal development or following intestinal tissue damage. The presence of fibroblasts in healthy tissue seems to stimulate the cancer cells to enter a defensive state, which protects them from chemotherapy. This happens really quickly, often within a couple of hours, so it’s easy to see why treatment fails to work. The cancer cells suffer damage, but they don’t die.”
Technical limitations previously meant researchers could only analyse a handful of different scenarios at a time. Mass cytometry and a new computational method, called TRELLIS, allowed the team to map the landscape of different cancers under various treatment and culture conditions.
The authors say that finding ways to force cancer cells into a fast-growing state prior to chemotherapy may be able to make the treatment more effective.