Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

• Published in: Nature cell biology Vol. 21; no. 2; pp. 190 - 202
• Main Authors: Keklikoglou, Ioanna, Cianciaruso, Chiara, Güç, Esra, Squadrito, Mario Leonardo, Spring, Laura M., Tazzyman, Simon, Lambein, Lore, Poissonnier, Amanda, Ferraro, Gino B., Baer, Caroline, Cassará, Antonino, Guichard, Alan, Iruela-Arispe, M. Luisa, Lewis, Claire E., Coussens, Lisa M., Bardia, Aditya, Jain, Rakesh K., Pollard, Jeffrey W., De Palma, Michele
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13; 13/31; 13/44; 13/95; 14/19; 14/28; 14/35; 631/67; 631/67/322; 631/67/327; 631/80/313/1481; 64/116; 64/60; 82/58; Adjuvant chemotherapy; Animal models; Animals; Annexin A6 - metabolism; Anthracycline; Anthracyclines; Antineoplastic agents; Biomedical and Life Sciences; Breast cancer; Calcium; Calcium ions; Cancer; Cancer cells; Cancer metastasis; Cancer Research; Cancer therapies; Cancer treatment; CCR2 protein; Cell activation; Cell Biology; Cell Line, Tumor; Chemokine CCL2 - metabolism; Chemotherapy; Complications and side effects; Cytotoxicity; Deactivation; Development and progression; Developmental Biology; Doxorubicin - therapeutic use; Drug therapy; Endothelial cells; Endothelium; Exosomes; Extracellular vesicles; Extracellular Vesicles - drug effects; Extracellular Vesicles - metabolism; Female; Health aspects; Humans; Inactivation; Invasiveness; Life Sciences; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Lungs; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medical schools; Metastases; Metastasis; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Mice, Transgenic; Monocyte chemoattractant protein 1; Monocytes; NF-κB protein; Organelles; Organs; Paclitaxel - therapeutic use; Proteins; Risk factors; Stem Cells; Taxanes; Tumors; Vesicles
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-018-0256-3

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours 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 tumour-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 tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca 2+ -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. Keklikoglou et al. report that cytotoxic drugs induce tumour-derived extracellular vesicles that facilitate monocyte expansion through annexin A6 and thus lung metastasis in breast cancer.