Here is why chemotherapy becomes less effective, finds study

Here is why chemotherapy becomes less effective, finds study
Two studies from Yale and UCL show that encouraging cancer cells to grow more slowly reduces the effectiveness of chemotherapy.

Researchers used mini-tumors and the most recent single-cell analysis technologies in the two trials, which were funded by Cancer Research UK and published in Cell, to start to unravel the mystery of why healthy cells in a patient's colon cancer tumour may contribute to unfavourable outcomes.

Over 900,000 people die from bowel cancer annually, making it the second most common cause of cancer-related death worldwide. It is responsible for 10% of cancer-related deaths in the UK.

Using the most recent single-cell analysis technologies, UCL researchers measured the response of 1,107 mouse-derived mini-tumours to modifications in gene and
Analysis revealed that bowel cancer cells can exist in two major states, 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. Our research suggests that because chemotherapies target fast-growing cells, cancer cells that have their growth slowed down by healthy cells are no longer sensitive to 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. Crucially, healthy fibroblast cells could slow down cancer growth in some patients, completely protecting the cancer from chemotherapy.

Dr Maria Ramos Zapatero, a first author on one of the studies from 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."

Professor Smita Krishnaswamy, a senior author of one of the studies from Yale University, said: "There has been a lot of research in recent years to understand what is happening in cancer cells and in the surrounding environment at the single-cell level. But previously technical limitations meant we could only analyse a handful of different scenarios at a time.

"This is a problem when you're dealing with thousands of variables, including cancer cells with different mutations, different therapies and the complex interaction between tumours and the cells around them. The mass cytometry workflow and our new computational method, called TRELLIS, creates a way of embedding samples from cytometry in such a way that distances between entire samples can be computed, allowing us to map the landscape of different cancers under various treatment and culture conditions. These technical advances have allowed us to see the big picture and help to explain why some cancers are less sensitive to treatment."

The authors say that finding ways to force cancer cells into a fast-growing state prior to a patient beginning a course of chemotherapy may be able to make the treatment more effective.

Dr Tape concluded: "By understanding the molecular processes driving this change, we may be able to develop ways to block communication between cancer cells and healthy cells in order to return the tumour to the fast-growing state, making the cancer sensitive to chemotherapies even in the presence of healthy cells. I think we now have a huge opportunity to improve outcomes for those whose bowel cancer is not or would not be easy to treat."