Hospitalized cancer patient undergoing chemotherapy.
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Researchers at Tel Aviv University have identified a mechanism generating a cancer-promoting inflammatory environment in response to chemotherapy and an anti-inflammatory treatment combination reducing the incidence of lung metastasis by nearly 50 percent.

Chemotherapy efficacy rates vary by cancer type and stage, ranging from recurrence rates of 30 percent in patients with B-cell lymphoma to 85 percent in ovarian cancer. However, the mechanisms behind the reasons for the relapses remain largely unknown and are therefore difficult to prevent. A team of scientists at Tel Aviv University is now aiming to change this.

Reporting in Nature Communications, the researchers developed an animal model for breast cancer metastasis. The animals underwent the same treatment as regular breast cancer patients by removal of the primary tumor followed by chemotherapy to eliminate the remaining cancer cells. Metastatic relapse was closely monitored to be detected as early possible in comparison to a control group that hadn’t received chemotherapy treatment.

Surprisingly, metastatic lung tumors were discovered in similar rates in the chemotherapy treated rats as well as the control group, leading the researchers to examine the animals’ lungs at an intermediate stage where micro-metastases may have already started forming, to pinpoint the reason for metastatic relapse and subsequent low efficacy of chemotherapy.

“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. The fibroblasts secrete ‘complement proteins’—proteins that mediate cell recruitment and intensify inflammation,” said professor Neta Erez, PhD, chair of pathology at Tel Aviv University and co-author of the study in a press statement.

“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.”

As a solution for the newly discovered mechanism, the researchers conducted another study administering chemotherapy combined with a drug that blocks the activity of ‘complement proteins’ in animal models. Following the treatment with the new chemotherapy, the animals showed a decrease in lung metastasis of 52 percent compared to six percent after the non-combined treatment.

“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. 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,” Erez concluded.

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