Combining chemotherapy with an anti-inflammatory drug can prevent breast cancer from metastasizing

Combining chemotherapy with an anti-inflammatory drug can prevent breast cancer from metastasizing

A new treatment developed at Tel Aviv University could significantly improve the effectiveness of chemotherapy in breast cancer patients, reducing the risk of lung metastases after chemotherapy from 52% to just 6%. The study, conducted in an animal model, identified the mechanism that creates a cancer-promoting inflammatory environment in response to chemotherapy. In addition, researchers found that adding an anti-inflammatory agent to chemotherapy can prevent metastasis.

The study was led by Prof. Neta Erez from the Department of Pathology at TAU's Sackler Faculty of Medicine and researchers from her group: Lea Monteran, Dr. Nour Ershaid, Yael Zait and Ye’ela Scharff in collaboration with Prof. Iris led Barshack from Sheba Medical Center and Dr. Amir Sonnenblick from Tel Aviv Sourasky (Ichilov) Medical Center. The paper was published in Nature Communications. The study was funded by the ERC, the Israel Cancer Association and the Emerson Cancer Research Fund.

In many cases of breast cancer, surgical removal of the primary tumor is followed by chemotherapy, which aims to kill any remaining malignant cells that have either been left behind by the surgeon or have already colonized other organs. Although chemotherapy is effective in killing cancer cells, it also has some unwanted and even harmful side effects, including damage to healthy tissue. The most dangerous of these is probably internal inflammation, which paradoxically could help remaining cancer cells metastasize to distant organs. The aim of our study was to find out how this happens and try to find an effective solution.”

Prof. Neta Erez, Department of Pathology, TAU Sackler Medical Faculty

To this end, the researchers created an animal model of breast cancer metastasis. The animals received the same treatment as human patients: surgical removal of the primary tumor, then chemotherapy, followed by monitoring to detect metastatic relapse as early as possible. The worrying result: Metastatic tumors were detected in the lungs in a large percentage of the treated animals - similar to the control group.

To decipher these side effects, the researchers examined the animals' lungs at an intermediate stage - when tiny micrometastases may have already formed but even advanced imaging techniques such as CT cannot detect them. Prof. Erez: "This period of time between chemotherapy and the detection of metastases is an inaccessible 'black box' in humans. Using an animal model, we were able to check what actually happens in this 'box'. We discovered a previously unknown mechanism: chemotherapy generates an inflammatory reaction in connective tissue cells, the so-called fibroblasts, which cause them to release immune cells from the Summon bone marrow. This, in turn, creates an inflammatory environment that supports the micrometastases and helps them develop into full-fledged metastatic tumors. Chemotherapy, administered as a means to fight cancer, achieves the opposite result.”

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The researchers also identified the mechanism by which fibroblasts recruit immune cells and “train” them to support the cancer. Prof. Erez: "We found that in response to chemotherapy, the fibroblasts secrete 'complement proteins' - proteins that mediate cell recruitment and intensify inflammation, often by summoning white blood cells to damaged or infected areas, a process called chemotaxis. When cells reach the lungs, they create an inflammatory environment that supports cancer cells and helps them grow.”

To combat this newly discovered process, researchers combined the chemotherapy administered to the animals with a drug that blocks the activity of complement proteins. The results were very encouraging: after the combined treatment, the percentage of animals that did not develop metastases increased from 32% to 67%; and the percentage of patients with extensive cancer in the lungs fell from 52% with regular chemotherapy to 6% when the anti-inflammatory drug was added.

Prof. Erez concludes: "We have discovered the mechanism behind a serious problem in the treatment of breast cancer: many patients develop metastatic tumors after removal of the primary tumor plus chemotherapy. We identified an inflammatory mechanism by which chemotherapy inadvertently promotes the growth of metastatic tumors, and also discovered an effective solution: the combination of a Chemotherapy with an anti-inflammatory drug. We hope that our findings will enable more effective treatment of breast cancer and perhaps other types of cancer – preventing metastatic relapse and saving many lives worldwide.”

Source:

Tel Aviv University

Reference:

Monteran, L., et al. (2022) Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nature communication. doi.org/10.1038/s41467-022-33598-x.

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