Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes

PLoS One. 2012;7(12):e50999. doi: 10.1371/journal.pone.0050999. Epub 2012 Dec 10.

Abstract

Background: Hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. Recent studies suggest that phenotypic changes associated with cancer may be transferred from cell-to-cell via microvesicles/exosomes. Here we aimed to investigate phenotypic changes associated with docetaxel-resistance in order to help determine the complexity of this problem and to assess the relevance of secreted exosomes in prostate cancer.

Methodology/principal findings: Docetaxel-resistant variants of DU145 and 22Rv1 were established and characterised in terms of cross-resistance, morphology, proliferation, motility, invasion, anoikis, colony formation, exosomes secretion their and functional relevance. Preliminary analysis of exosomes from relevant serum specimens was also performed. Acquired docetaxel-resistance conferred cross-resistance to doxorubicin and induced alterations in motility, invasion, proliferation and anchorage-independent growth. Exosomes expelled from DU145 and 22Rv1 docetaxel-resistant variants (DU145RD and 22Rv1RD) conferred docetaxel-resistance to DU145, 22Rv1 and LNCap cells, which may be partly due to exosomal MDR-1/P-gp transfer. Exosomes from prostate cancer patients' sera induced increased cell proliferation and invasion, compared to exosomes from age-matched controls. Furthermore, exosomes from sera of patients undergoing a course of docetaxel treatment compared to matched exosomes from the same patients prior to commencing docetaxel treatment, when applied to both DU145 and 22Rv1 cells, showed a correlation between cellular response to docetaxel and patients' response to treatment with docetaxel.

Conclusions/significance: Our studies indicate the complex and multifaceted nature of docetaxel-resistance in prostate cancer. Furthermore, our in vitro observations and preliminary clinical studies indicate that exosomes may play an important role in prostate cancer, in cell-cell communication, and thus may offer potential as vehicles containing predictive biomarkers and new therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Docetaxel
  • Drug Resistance, Neoplasm / physiology*
  • Exosomes / drug effects*
  • Exosomes / genetics
  • Humans
  • Male
  • Phenotype
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Taxoids / pharmacology*
  • Taxoids / therapeutic use

Substances

  • Taxoids
  • Docetaxel

Grants and funding

This research was supported by Science Foundation Ireland's funding of Strategic Research Cluster, Molecular Therapeutics for Cancer Ireland (08/SRC/B1410) to JC, WW, LOD; funding, to LOD, to support KOB as a Marie Keating Foundation Scholarship at Trinity College Dublin; and infrastructure and core facility support through Ireland's HEA's Programme for Research in Third Level Institutes (PRTLI) Cycle 5 to LOD among other TCD PIs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.