Chemotherapy is effective in treating invasive breast cancer. But can it also cause metastasis? Experimental studies in mice have suggested that this may be the case. In a further investigation of this matter, an international team of researchers has shown that two classes of chemotherapy drugs used in neoadjuvant (pre-operative) breast cancer therapy, taxanes and anthracyclines, cause tumors to release extracellular vesicles (EVs) such as exosomes that can enable the seeding and growth of metastatic cancer cells in distant organs.
Primary tumors release EVs, including exosomes, without the influence of chemotherapy. However, the authors of the study, published in Nature Cell Biology, found that compared with EVs from chemotherapy-naive tumors, chemotherapy-induced EVs have greater quantities of annexin A6, a protein that facilitates lung metastasis.
"It seems that loading of annexin A6 into exosomes is significantly enhanced in response to chemotherapy," commented the study's first author, Ioanna Keklikoglou, PhD, Professor at the Swiss Institute for Experimental Cancer Research (ISREC), part of the School of Life Sciences of the École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland.
The researchers found that annexin A6 is present and possibly enriched in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy. When the circulating EVs reach the lung and release annexin A6, the lung cells then release CCL2, a protein that attracts immune cells called monocytes. Monocytes can enable the survival and growth of cancerous cells in the lung, beginning the process of metastasis.
"In short, our study has identified a new link between chemotherapy and breast cancer metastasis," stated another of the study's authors, Michele De Palma, PhD, Associate Professor at ISREC.
The researchers have found a potential solution to this problem: inactivating either the gene that produces annexin A6 in cancer cells or the gene that produces CCL2 in the host cells reduces the metastasis-promoting effects of chemotherapy-elicited EVs.
"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," remarked Dr. De Palma.
For More Information
Keklikoglou I, Cianciaruso C, Güç E, et al (2018). Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat Cell Bio. [Epub ahead of print] DOI:10.1038/s41556-018-0256-3
Image courtesy of C. Cianciaruso & I. Keklikoglou, École Polytechnique Fédérale de Lausanne