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

• Published in: PloS one 2012-12, Vol.7 (12), p.e50999-e50999
• Main Authors: Corcoran, Claire, Rani, Sweta, O'Brien, Keith, O'Neill, Amanda, Prencipe, Maria, Sheikh, Rizwan, Webb, Glenn, McDermott, Ray, Watson, William, Crown, John, O'Driscoll, Lorraine
• Format: Article
• Language: English
• Subjects: Analysis; Androgens; Anoikis; Anthracyclines; Biomarkers; Cancer; Cell cycle; Cell interactions; Cell Line, Tumor; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cell signaling; Communication; Complexity; Cross-resistance; Development and progression; Docetaxel; Doxorubicin; Drug Resistance, Neoplasm - physiology; Exosomes; Exosomes - drug effects; Exosomes - genetics; Humans; Male; MDR1 protein; Medicine; Morphology; Motility; P-Glycoprotein; Patients; Pharmaceutical sciences; Pharmacy; Phenotype; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Secretion; Signal transduction; Taxoids - pharmacology; Taxoids - therapeutic use; Wound healing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0050999

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. 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. 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.