Chemotherapy-Induced Upregulation of Small Extracellular Vesicle-Associated PTX3 Accelerates Breast Cancer Metastasis

Cancer Res. 2021 Jan 15;81(2):452-463. doi: 10.1158/0008-5472.CAN-20-1976. Epub 2020 Oct 28.


Although neoadjuvant chemotherapy is a standard component of breast cancer treatment, recent evidence suggests that chemotherapeutic drugs can promote metastasis through poorly defined mechanisms. Here we utilize xenograft mouse models of triple-negative breast cancer to explore the importance of chemotherapy-induced tumor-derived small extracellular vesicles (sEV) in metastasis. Doxorubicin (DXR) enhanced tumor cell sEV secretion to accelerate pulmonary metastasis by priming the premetastatic niche. Proteomic analysis and CRISPR/Cas9 gene editing identified the inflammatory glycoprotein PTX3 enriched in DXR-elicited sEV as a critical regulator of chemotherapy-induced metastasis. Both genetic inhibition of sEV secretion from primary tumors and pharmacologic inhibition of sEV uptake in secondary organs suppressed metastasis following chemotherapy. Taken together, this research uncovers a mechanism of chemotherapy-mediated metastasis by which drug-induced upregulation of sEV secretion and PTX3 protein cargo primes the premetastatic niche and suggests that inhibition of either sEV uptake in secondary organs or secretion from primary tumor cells may be promising therapeutic strategies to suppress metastasis. SIGNIFICANCE: These findings show that chemotherapy-induced small extracellular vesicles accelerate breast cancer metastasis, and targeted inhibition of tumor-derived vesicles may be a promising therapeutic strategy to improve the efficacy of chemotherapy treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism*
  • Cell Movement
  • Cell Proliferation
  • Doxorubicin / adverse effects*
  • Extracellular Vesicles / drug effects
  • Extracellular Vesicles / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Serum Amyloid P-Component / genetics
  • Serum Amyloid P-Component / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antibiotics, Antineoplastic
  • Biomarkers, Tumor
  • Serum Amyloid P-Component
  • PTX3 protein
  • Doxorubicin
  • C-Reactive Protein