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Nat Cell Biol. 2018 Dec 31. doi: 10.1038/s41556-018-0256-3. [Epub ahead of print]

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models.

Author information

1
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. ioanna.keklikoglou@epfl.ch.
2
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
3
MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
4
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
5
Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK.
6
Department of Cell, Developmental and Cancer Biology, Oregon Health and Sciences University, Portland, OR, USA.
7
Edwin L. Steele Laboratories, Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
8
Department of Molecular Cell and Developmental Biology, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
9
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
10
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, NY, USA.
11
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. michele.depalma@epfl.ch.

Abstract

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 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.

PMID:
30598531
DOI:
10.1038/s41556-018-0256-3

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