Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models.
Ioanna KeklikoglouChiara CianciarusoEsra GüçMario Leonardo SquadritoLaura M SpringSimon TazzymanLore LambeinAmanda PoissonnierGino B FerraroCaroline BaerAntonino CassaráAlan GuichardM Luisa Iruela-ArispeClaire E LewisLisa M CoussensAditya BardiaRakesh K JainJeffery W PollardMichele De PalmaPublished in: Nature cell biology (2018)
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.
Keyphrases
- locally advanced
- squamous cell carcinoma
- neoadjuvant chemotherapy
- small cell lung cancer
- rectal cancer
- patients undergoing
- radiation therapy
- dendritic cells
- endothelial cells
- induced apoptosis
- stem cells
- oxidative stress
- type diabetes
- drug delivery
- dna methylation
- gene expression
- pulmonary hypertension
- insulin resistance
- adipose tissue
- skeletal muscle
- cell proliferation
- combination therapy
- cell cycle arrest
- cell death
- nuclear factor
- high glucose
- high fat diet induced
- case control