New treatment could increase efficacy of chemo, prevent metastasis - TAU study

The number of women who recover from this malignancy is steadily on the rise, thanks to early detection, enhanced treatment techniques and heightened awareness.

 An image of lung with breast cancer metastasis, surrounded by inflammatory complement protein: Cyan: Cell nuclei; Red: Complement protein; Green: blood vessels; (photo credit: LEA MONTERAN)
An image of lung with breast cancer metastasis, surrounded by inflammatory complement protein: Cyan: Cell nuclei; Red: Complement protein; Green: blood vessels;
(photo credit: LEA MONTERAN)

Breast cancer is the most common malignant disease in Israel and the Western world. One out of eight Israeli women contract it during their lifetime, and about 4,500 are diagnosed with and 900 die of it every year.  

The number of women who recover from this malignancy is steadily on the rise, thanks to early detection, enhanced treatment techniques and heightened awareness – and the earlier the disease is detected, the higher the chances of recovery, reaching nearly 90%. 

Working on an animal model, Tel Aviv University (TAU) researchers identified a mechanism that generated a cancer-promoting inflammatory environment in response to chemotherapy. Based on this discovery, they developed a treatment combination that reduced the incidence of lung metastasis (spreading) following chemotherapy from 52% to only 6%. Lungs are one of the most common sites of breast cancer metastasis, conferring a median survival of less than two years after diagnosis.

This discovery, they said, could significantly enhance the efficacy of chemotherapy in breast cancer patients, reducing the risk for lung metastasis following chemo in this malignancy as well. Moreover, the researchers found that by adding an anti-inflammatory agent to the chemotherapy, metastasis can be prevented.

Who was the study led by?

(Left to right): Dr. Nour Ershaid, Prof. Neta Erez & Lea Monteran (credit: TEL AVIV UNIVERSITY)(Left to right): Dr. Nour Ershaid, Prof. Neta Erez & Lea Monteran (credit: TEL AVIV UNIVERSITY)

The study was led by Prof. Neta Erez of the pathology department 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 Barshack of the Sheba Medical Center at Tel Hashomer and Dr. Amir Sonnenblick of the Tel Aviv Sourasky Medical Center. The paper was published in Nature Communications under the title “Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer.”

“In many cases of breast cancer, surgical removal of the primary tumor is followed by a chemotherapy regimen intended to kill any remaining malignant cells – either left behind by the surgeon or already colonizing in other organs,” Erez said.

“However, while effectively killing cancer cells, chemotherapy also has some undesirable and even harmful side effects, including damage to healthy tissues. The most dangerous of these is probably internal inflammation that could paradoxically help remaining cancer cells to form metastases in distant organs. The goal of our study was to discover how this happens and try to find an effective solution.”

The rodents 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 disturbing results were that metastatic tumors were detected in the lungs of a large percentage of the treated animals, similar to the percentage found in the control group.

TO UNDERSTAND the basis for these adverse effects, the researchers examined the animals’ lungs at an intermediate stage – when tiny micro-metastases may have already developed, but even advanced imaging technologies like computerized tomography (CT) can’t detect them.

“In humans, this interval between chemotherapy and detection of metastatic tumors is an inaccessible ‘black box.’ Working with an animal model, we could check what actually happens inside this ‘box,’” Erez explained.

“We discovered a previously unknown mechanism – the chemotherapy generates an inflammatory response in connective tissue cells called fibroblasts, causing them to summon immune cells from the bone marrow. This in turn creates an inflammatory environment that supports the micro-metastases, helping them grow into full-fledged metastatic tumors. In this way, the chemotherapy, administered as a means for combating cancer, achieves the opposite result.”

The researchers also identified the mechanism through which fibroblasts recruit immune cells, and “train” them to support cancer. “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,” she explained. “When the immune cells reach the lungs, they create an inflammatory environment that supports cancer cells and helps them grow.”

To combat this newly discovered process, the researchers combined the chemotherapy given 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 developing no metastases rose from a third to two-thirds (32% to 67%), and the percentage of those with extensive cancer colonization in their lungs decreased from 52% with regular chemotherapy to 6% when the inflammation inhibitor was added.

“We discovered the mechanism behind a severe problem in the treatment of breast cancer: Many patients develop metastatic tumors following removal of the primary tumor plus chemotherapy. We identified an inflammatory mechanism through which chemotherapy inadvertently supports the growth of metastatic tumors, and also discovered an effective solution: combining chemotherapy with an inflammation inhibitor,” Erez concluded.

“We hope that our findings will enable more effective treatment for breast cancer and perhaps other types of cancer as well – to prevent metastatic relapse and save numerous lives worldwide.”