The new treatment can significantly improve the efficacy of chemotherapy for breast cancer and prevent metastasis

A new treatment developed by Tel Aviv University could significantly improve chemotherapy in breast cancer patients, reducing the risk of lung metastases after chemotherapy from 52 percent to just 6 percent
.
Studies conducted in animal models have identified the mechanisms
that produce the response to chemotherapy in the inflammatory environment that promotes cancer.
In addition, the researchers found that metastasis
could be prevented by adding anti-inflammatory agents to chemotherapy.

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

Professor Erez: "In many breast cancer cases, surgery to remove the primary tumour is followed by chemotherapy to kill any remaining malignant cells – either left by surgeons or already colonized in other organs
.
However, while effectively killing cancer cells, chemotherapy also has some undesirable and even harmful side effects, including damage
to healthy tissue.
The most dangerous of these may be inflammation in the body, which may paradoxically help remaining cancer cells form metastases
in distant organs.
The goal of our research is to discover how this happens and try to find effective solutions
.
”

To do this, the researchers created an animal model
of breast cancer metastasis.
The animals received the same treatment as human patients: surgery to remove the primary tumor, followed by chemotherapy, and then monitoring to detect metastatic recurrence
early.
The troubling result: a large proportion of metastatic tumors were found in the lungs of the treated animals — similar
to the proportions found in the control group.

To decipher these adverse effects, the researchers examined the animals' lungs at an intermediate stage — when tiny micrometastases may have occurred, but even advanced imaging techniques like CT can't detect them
.
Professor Erez: "In humans, the period between chemotherapy and the discovery of metastatic tumours is an inaccessible 'black box'
.
Through animal models, we can examine what exactly is going on
in this box.
We discovered a previously unknown mechanism: chemotherapy creates 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 micrometastases, helping them grow into mature metastatic tumors
.
In this way, chemotherapy, as a means of fighting cancer, has achieved the opposite result
.
”

The researchers also identified the mechanisms
by which fibroblasts recruit immune cells and "train" them to support cancer.
Professor Erez said: "We found that in response to chemotherapy, fibroblasts secrete 'complement proteins' – proteins that mediate the recruitment of cells and exacerbate inflammation, usually by summoning white blood cells to damaged or infected areas, a process known as chemotaxis
.
When immune cells reach the lungs, they create an inflammatory environment that supports cancer cells and helps them grow
.
”

To counter this newly discovered process, the researchers combined
chemotherapy given to the animals with a drug that blocks complement protein activity.
The results were very encouraging: after combination therapy, the proportion of animals without metastases increased from 32% to 67%; For those with extensive cancer colonization of the lungs, the proportion dropped from 52 percent with conventional chemotherapy to 6 percent
with the addition of inflammatory suppressants.

Professor Erez concluded: "We have discovered the mechanism behind a serious problem in breast cancer treatment: many patients develop metastatic tumours
after removal of the primary tumour plus chemotherapy.
We discovered an inflammatory mechanism by which chemotherapy inadvertently supported the growth of metastatic tumors and found an effective solution: combining
chemotherapy with inflammatory suppressants.
We hope that our findings will contribute to more effective treatments for breast cancer, and perhaps other types of cancer, to prevent metastatic recurrence and save countless lives
worldwide.
" ”

Lea Monteran, Nour Ershaid, Hila Doron, Yael Zait, Ye’ ela Scharff, Shahar Ben-Yosef, Camila Avivi, Iris Barshack, Amir Sonnenblick, Neta Erez.
Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer.
Nature Communications, 2022; 13 (1)