title: Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Claire
authors.initials: C
authors.lastname: Corcoran
authors.forename: Sweta
authors.initials: S
authors.lastname: Rani
authors.forename: Keith
authors.initials: K
authors.lastname: O'Brien
authors.forename: Amanda
authors.initials: A
authors.lastname: O'Neill
authors.forename: Maria
authors.initials: M
authors.lastname: Prencipe
authors.forename: Rizwan
authors.initials: R
authors.lastname: Sheikh
authors.forename: Glenn
authors.initials: G
authors.lastname: Webb
authors.forename: Ray
authors.initials: R
authors.lastname: McDermott
authors.forename: William
authors.initials: W
authors.lastname: Watson
authors.forename: John
authors.initials: J
authors.lastname: Crown
authors.forename: Lorraine
authors.initials: L
authors.lastname: O'Driscoll
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055354:Exosomes / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D043823:Taxoids; D000077143:Docetaxel