An international team of researchers led by Michele De Palma, PhD, at the Ecole Polytechnique Federale De Lausanne (EPFL) says it has shed new light on the process of neoadjuvant therapy, which is chemotherapy given to breast cancer patients before surgery to help reduce the size of the tumor and facilitate breast conservation.

But not all tumors shrink under chemotherapy. If the tumor resists neoadjuvant therapy, there can be a higher risk of developing metastatic disease, meaning that the tumor will recur in other organs, such as bones or lungs. This could be due to cancerous cells that resist chemotherapy and spread to other organs while the primary tumor is being treated.

Working with experimental tumor models, the scientists found that two chemotherapy drugs frequently used for patients, paclitaxel and doxorubicin, induce mammary tumors to release exosomes. Under chemotherapy, the exosomes contain the protein annexin-A6, which is not present in the exosomes released from untreated tumors. “It seems that loading of annexin-A6 into exosomes is significantly enhanced in response to chemotherapy,” explained Ioanna Keklikoglou, PhD, first author of the study.

The researchers’ study (“Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models”) appears in Nature Cell Biology.

“Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumors release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumor-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumor-derived EVs with enhanced pro-metastatic capacity,” wrote the investigators.

“Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction, and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of ANXA6 in cancer cells or Ccr2 in host cells blunts the pro-metastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy.”

After being released from a chemotherapy-treated tumor, the exosomes circulate in the blood. Upon reaching the lung, the exosomes release their content, including annexin-A6. This stimulates the lung cells to release another protein, Ccl2 which attracts immune cells called monocytes.

This immune reaction can be dangerous, as previous studies have shown that monocytes can facilitate the survival and growth of cancerous cells in the lung, which is one of the initial steps in metastasis. “In short, our study has identified a new link between chemotherapy and breast cancer metastasis,” said De Palma.

The team also found increased levels of annexin-A6 in the exosomes of breast cancer patients undergoing neoadjuvant chemotherapy. However, De Palma cautions against jumping to conclusions: “While this observation supports the significance of our findings, at the moment we don’t know if annexin-A6 has any pro-metastatic activity in human breast cancer.”

In addition, the researchers found that neutralizing annexin-A6 or blocking monocytes during chemotherapy prevents the experimental mammary tumors from metastasizing to the lung. These results may help to improve the efficacy and safety of neoadjuvant chemotherapy. “Various monocyte inhibitors have been developed for clinical use, so they may be tested in combination with neoadjuvant chemotherapy to potentially limit unwanted side effects mediated by exosomes,” said De Palma.

The team stresses that its findings must not discourage patients from receiving neoadjuvant chemotherapy when it’s indicated, calling it “essential and potentially curative treatment for many invasive breast cancers, as shown by multiple clinical trials.”

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