How cancer cells hide from chemotherapy

Cells that divide in a normal intestine are only present in certain areas within the tissue.

When the cells migrate away from these areas, they change and lose their ability to divide and begin to absorb nutrients instead.

New research shows that cancer cells behave similarly but still do not lose the ability to divide.

Detailed analysis of these cancer cells demonstrates that they are instead able to establish a special local environment that enables them to continue dividing.

By blocking the signals to this local environment, the researchers reveal that these cancer cells can be targeted despite being otherwise able to survive traditional chemotherapy.

The discovery may lead to more effective combination therapy for combatting cancer.

“Others may take the next step towards developing an actual anticancer treatment that targets the opportunities for cancer cells to grow, but we have identified an interesting mechanism to pursue,” explains Kim Bak Jensen, Professor, Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen.

The research has been published in Gastroenterology.

Studied cell signalling in cancer

Kim Bak Jensen and his colleagues investigated why tumour cells, unlike normal cells, can continue to divide.

In normal tissue, bone morphogenic protein (BMP) signalling regulates whether cells can divide or not. When cells in healthy tissue are exposed to BMP, they lose this ability.

The regulation takes place down to the stem cell level, in which BMP signals to the stem cells and their daughter cells that there are sufficient cells in, for example, the intestine, and that instead of dividing, the cells should form a barrier against the environment and start absorbing nutrients.

Once the cells have received this signal, they never divide again, even if BMP is no longer there. However, this normal mechanism is deactivated in cancer.

“In our mouse models, tumour cells and healthy cells behave differently. When we expose healthy cells to BMP, they stop dividing, but tumour cells do not. When the tumour cells are exposed to BMP, they seem to become functional, cease cell division and start to absorb nutrients. However, they continue to divide as soon as the signal disappears,” says Kim Bak Jensen.

Cancer cells survive chemotherapy

The discovery is very important in relation to anticancer treatment because it often targets cells that divide uninhibitedly. However, not all cancer cells divide.

In a tumour, cells exposed to BMP retain the capacity to divide but do not divide and are thus not vulnerable to chemotherapy. The chemotherapy will instead eliminate all the dividing cells.

When chemotherapy kills these dividing cells in the tumour, physical spaces open up in which there is no BMP. The cancer cells, which until then had not divided, take advantage of this by moving into these spaces, where they can now start dividing again.

“This means that the tumour has identified an escape mechanism by which it becomes less vulnerable to chemotherapy, because some cells are always left behind not dividing. When the BMP signal disappears again, cell division begins and the tumour can then continue to grow,” explains Kim Bak Jensen.

Protein plays a key role in tumour defence

The researchers examined how the tumour cells differ from healthy cells by examining differences in genetic expression between healthy and cancer cells.

The results showed that several genetic factors related to the extracellular matrix differ between cancer cells and healthy cells.

The extracellular matrix is a network of proteins that surrounds the cells and is specifically upregulated in the tumour cells. They thereby create their own unique microenvironment, which turns out to be crucial for their survival.

Fibronectin may be a target for anticancer therapy

The researchers examined fibronectin, a protein that is part of the extracellular matrix, and discovered that tumour cells have considerable fibronectin in their extracellular matrix.

The researchers observed that healthy cells exposed to fibronectin no longer responded to the signal from BMP and could divide again when BMP was removed from the medium.

Otherwise, fibronectin had no effect on the tumour cells, but when the researchers pharmaceutically removed the signal from fibronectin in the tumour cells, they became susceptible to BMP and could no longer divide.

Kim Bak Jensen hopes that the discovery can be used to create more effective anticancer treatments that both target the dividing cells with chemotherapy and remove signals from the extracellular matrix.

“In our experiments, we used an inhibitor that blocks the signal from fibronectin. This drug is currently being investigated in clinical trials focusing on other diseases. This may be an opportunity to investigate the drug in connection with combination treatment for people with cancer,” says Kim Bak Jensen.

Kim Bak Jensen also emphasises that the researchers have so far only studied the mechanism in cancer cells from the intestine and that determining whether the same mechanism is active in other types of cancer will be important.

The study 'Extracellular matrix interactions provide tumor cells with an escape mechanism for commitment to differentiation' was published in the journal Gastroenterology.

This news article was written by Kristian Sjøgren and originally published in sciencenews.dk on October 25, 2022.

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