Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Abstract

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest pro-metastatic effects of chemotherapy. 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-kB-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.

A stroma‐related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early‐stage colon cancer

“…Notably, in subtype 3 patients, ADJC did not benefit patients and even increased the mortality risk by 2.16 times. We speculated that it might be due to the fact that chemotherapy itself increased the metastatic potential of the drug‐resistant cells, and accelerated tumour progression . Therefore, research on developing new strategies for subtype 3 patients is warranted.…”

“…We speculated that it might be due to the fact that chemotherapy itself increased the metastatic potential of the drug-resistant cells, and accelerated tumour progression. 35,36 41 As for MIR31HG, Eide et al found that MIR31HG was an independent prognostic factor for patients with colon cancer. 42 Meanwhile, the cell lines with high MIR31HG outlier expression were characterized by an elevated EMT signature and TGFβ signalling activation.…”

The cancer exosomes: Clinical implications, applications and challenges

“…Lung premetastatic niche constructed by primary tumor-derived exosomes benefits cancer metastasis. Keklikoglou et al 44 also showed that breast cancer-derived annexin A6 (ANXA6) in chemotherapy-treated exosomes stimulated NF-kappaB-dependent endothelial cell, induced Ccl2 and broaden Ly6C(+)CCR2(+) monocyte in the pulmonary premetastatic niche to facilitate lung metastasis stimulates endothelial cells (Table 1). Lobb et al 45 detected tumor exosomal RNAs through and showed that exosomes enriched in RNAs could stimulate Toll-like receptor 3 (TLR3) in lung epithelial cells, which was conducive to release chemokine in the lung and recruited neutrophil.…”

“…Lung premetastatic niche constructed by primary tumor‐derived exosomes benefits cancer metastasis. Keklikoglou et al . also showed that breast cancer‐derived annexin A6 (ANXA6) in chemotherapy‐treated exosomes stimulated NF‐kappaB‐dependent endothelial cell, induced Ccl2 and broaden Ly6C(+)CCR2(+) monocyte in the pulmonary premetastatic niche to facilitate lung metastasis stimulates endothelial cells (Table ).…”

Monitoring Therapy Efficiency in Cancer through Extracellular Vesicles

“…Many studies confirm primary tumors to release EVs actively, thus helping the formation of pre-metastatic niche and enhancing metastasis [1,[25][26][27]. Keklikoglou et al [28] (Table 1) analyzed the effect of taxanes and anthracyclines, commonly used cytostatics in neoadjuvant treatment of BC, on secreting tumor-derived EVs with enhanced pro-metastatic capacity. They showed that chemotherapy-secreted EVs could promote NF-kb-dependent endothelial cell activation in an Annexin A6 dependent manner and induce CcL2 as well as and Ly6C + CCR2 + monocyte expansion, resulting in the establishment of lung metastasis of BC cancer cells.…”