Breast cancer recurrence may be triggered by chemotherapy injury to non-cancer cells

A standard chemotherapy drug injures surrounding non-cancer cells, which can then awaken dormant cancer cells and promotes cancer growth, according to a new study publishing September 12 in the open access journal PLoS Biology by Ramya Ganesan of Emory University, US, and colleagues. The finding is important for understanding cancer recurrence and may point to important new targets to prevent it.

Advances in cancer treatment, including chemotherapy, have dramatically reduced mortality for many types of cancer, including breast cancer. Nonetheless, up to 23% of breast cancer patients experience recurrence within the first five years. Treatment is meant to kill all cancer cells, but often, some cells enter a state of dormancy, in which they stop dividing and become unresponsive to chemotherapeutic agents. Recurrence occurs when dormant cells re-awaken and start dividing again.

Some studies have indicated that chemotherapy itself may promote escape from dormancy, but the mechanism of this effect has not been clear.

To explore that question, the authors worked with both a cell model and a mouse model of breast cancer. Importantly, the cell model contained both cancer cells and non-cancer stromal cells, connective tissue cells that are found in breast and other tissue. They administered the chemotherapy drug docetaxel at physiologically relevant concentrations, and found that even at very low doses, stromal cells were injured, while cancer cells were not, and that treatment induced cell-cycle reentry in cancer cells.

The driver of this reawakening of dormant cells, the authors showed, was release of two key cell signaling molecules, granulocyte colony stimulating factor (G-CSF) and interleukin-6 (IL-6) by the injured stromal cells, which acted on the dormant cells to promote their growth, both in vitro and in vivo.

That provided the team with potential anti-cancer targets, and they showed that antibodies that neutralized either G-CSF or IL-6, or a drug that blocked the mediator of those signals within cancer cells, inhibited awakening from dormancy due to docetaxel treatment.

These findings have several important implications. First, they highlight the importance of surrounding cells, not just the cancer cells themselves, in determining the response to chemotherapy. Second, they provide a possible mechanistic foundation for the observation that high serum levels of IL-6 are associated with early recurrence in breast cancer patients receiving chemotherapy, potentially strengthening the utility of that biomarker in planning treatment. Third, they provide new targets for preventing recurrence.

Dr. Ganesan and Dr.Sukhatme add, “Our paper highlights a deleterious effect of cancer chemotherapy: release of stromal IL-6 and G-CSF by taxane chemotherapy awakened dormant breast cancer cells, a postulated mechanism for tumor relapse. Transient blockade of cytokine signaling during chemotherapy administration may prevent tumor recurrence.”

More information: Ganesan R, Bhasin SS, Bakhtiary M, Krishnan U, Cheemarla NR, Thomas BE, et al. (2023) Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape. PLoS Biology (2023). DOI: 10.1371/journal.pbio.3002275

Citation: Breast cancer recurrence may be triggered by chemotherapy injury to non-cancer cells (2023, September 12) retrieved 13 September 2023 from https://medicalxpress.com/news/2023-09-breast-cancer-recurrence-triggered-chemotherapy.html

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02

Chemotherapy at home – the future of cancer care?

When Pat Randall was diagnosed as having cancer, he feared he would have to face daily treks to hospital for chemotherapy.

But after having surgery on his colon, the 58-year old journalist, who is married and lives in Winterbourne, eight miles outside Bristol, was told he would be one of the first people in the country to have the debilitating treatment at home.

‘It’s far less stressful,’ he says.

‘Even the thought of driving to the city centre hospital and daily battling against traffic was a nightmare. Having the treatment at home makes me feel much more relaxed about the illness.’

Chemotherapy is a mainstay cancer treatment and involves mixing drugs and administering them either orally or into a vein with the aim of stopping the growth of the cancer cells. Sometimes it is the only possible treatment, but it is also given after surgery on the tumour.

But chemotherapy can have a wide range of side-effects, including nausea, lethargy, depression, and hair loss, and for many cancer sufferers having to travel and from hospital for the treatment is highly stressful, causing anxiety as well as disrupting their everyday life.

Research shows that patients feel more relaxed when chemotherapy is given at home, and it is estimated that up to one in four UK patients in hospitals who is now receiving chemotherapy could benefit from being treated at home.

Doctors believe that in some cases, the more relaxed, less stressed dealing with the illness is, the speedier the recovery. But few people were in a position to have their treatment at home.

Now a new national service is being

launched by BUPA and Healthcare at Home which is designed to allow some cancer patients to receive chemotherapy in their own home from a team of specialist nurses.The treatment, available to three million people, can also be given at the patient’s office or elsewhere if they are staying away from home.

‘There is no doubt that, where appropriate, the vast majority of patients prefer to receive their treatment at home.

‘Our experienced nurses will administer treatment and remain with the patient throughout, which can take anything from 20 minutes to ten hours. ‘Between the chemotherapy sessions, patients who encounter any problems or anxieties can contact their personal nurse round-the- clock for support, or ask them to visit,’ says Ruth Poole, nursing director of Healthcare at Home

Pat Randall was diagnosed with colon cancer in January and had surgery the same month. He is now undergoing six months of chemotherapy.

‘I didn’t realise it was possible to have chemotherapy at home,’ says Pat, who has two daughters and four grandchildren.

‘But I had a talk with the oncologist in Bristol, and it was decided it would be suitable to have the treatment at home, and it has been brilliant.

‘The traffic is terrible, there is never anywhere to park, and you don’t want to deal with that kind of thing when you are having treatment. For some of the time I would have had to do that journey on a daily basis, and it would have been totally horrendous.’

The specialist nurse which now treats him at his home in Bristol gives him two types of drugs which are delivered every fortnight through a line attached to a vein in his arm.

The process takes about two hours, and the drug is pumped out of special pouch he wears for the next few hours.

‘First, they flush the line to see if everything is OK. Then they follow that up with a vitamin in solution, and finally they put through the chemotherapy. The nurse is here for about two hours and then I have to wear a pump with a chemotherapy sachet around the waist,’ he says.

‘It pumps out the chemo, and I have to wear it for 46 hours while it is doing its job. Two days later, the nurse comes back and disconnects me and checks that everything is all right. Later, a blood sample is taken to make sure everything is OK before the next dose is given.

‘I know you can get many sideeffects with chemotherapy, but the main one I am getting is fatigue, and even the thought of having to drive into Bristol to get treatment would add to that. There is nothing like being at home surrounded by family and friends when you are ill.’

Just how many people could benefit from the service is not clear, but increasing research showing the beneficial effects it has is likely to make home treatment more widely available.

‘We believe there is tremendous scope to increase the number of patients receiving chemotherapy at home,’ says Dr Chris Dickson of BUPA.

The cost of the home chemotherapy varies according to need and is covered by health insurance. But it is also available at a few NHS hospitals.

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03

Breast cancer recurrence: Could chemotherapy cause what it’s trying to stop?

Our paper highlights a deleterious effect of cancer chemotherapy: release of stromal IL-6 and G-CSF by taxane chemotherapy awakened dormant breast cancer cells, a postulated mechanism for tumor relapse

Ramya Ganesan, Vikas P. Sukhatme

Some studies have indicated that chemotherapy itself may promote escape from dormancy, but the mechanism of this effect has not been clear. To explore that question, the authors worked with both a cell model and a mouse model of breast cancer. Importantly, the cell model contained both cancer cells and non-cancer stromal cells, connective tissue cells that are found in breast and other tissue. They administered the chemotherapy drug docetaxel at physiologically relevant concentrations, and found that even at very low doses, stromal cells were injured, while cancer cells were not, and that treatment induced cell-cycle reentry in cancer cells.

The driver of this reawakening of dormant cells, the authors showed, was release of two key cell signaling molecules, granulocyte colony stimulating factor (G-CSF) and interleukin-6 (IL-6) by the injured stromal cells, which acted on the dormant cells to promote their growth, both in vitro and in vivo. That provided the team with potential anti-cancer targets, and they showed that antibodies that neutralized either G-CSF or IL-6, or a drug that blocked the mediator of those signals within cancer cells, inhibited awakening from dormancy due to docetaxel treatment.

These findings have several important implications. First, they highlight the importance of surrounding cells, not just the cancer cells themselves, in determining the response to chemotherapy. Second, they provide a possible mechanistic foundation for the observation that high serum levels of IL-6 are associated with early recurrence in breast cancer patients receiving chemotherapy, potentially strengthening the utility of that biomarker in planning treatment. Third, they provide new targets for preventing recurrence.

Dr. Ganesan and the paper’s last author, Dr. Vikas P. Sukhatme add, “Our paper highlights a deleterious effect of cancer chemotherapy: release of stromal IL-6 and G-CSF by taxane chemotherapy awakened dormant breast cancer cells, a postulated mechanism for tumor relapse. Transient blockade of cytokine signaling during chemotherapy administration may prevent tumor recurrence.”

Source: PLOS

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