Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

Cell Oncol (Dordr). 2020 Feb;43(1):123-136. doi: 10.1007/s13402-019-00476-6. Epub 2019 Nov 12.

Abstract

Purpose: Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance.

Methods: GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo.

Results: BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes.

Conclusions: Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

Keywords: Cancer stem cells; Drug resistance; Exosomes; Gemcitabine; MicroRNA-210; Pancreatic cancer.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Exosomes / drug effects*
  • Exosomes / genetics
  • Exosomes / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microscopy, Electron, Transmission
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / ultrastructure
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antineoplastic Agents
  • MIRN210 microRNA, human
  • MicroRNAs
  • Deoxycytidine
  • gemcitabine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases