Abstract
BackgroundHormone-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 FindingsDocetaxel-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/SignificanceOur 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.
Highlights
While docetaxel offers improvement in overall survival for patients with hormone-refractory prostate cancer (HRPC) as evident from two Phase III trials (TAX 327 and SWOG 9916) and subsequent clinical management, relapse is almost inevitable
Docetaxel-resistant Cells Demonstrate Some Cross Resistance to Other Anti-cancer Agents. Both resistant cell line variants exhibited cross-resistance (4–8 fold) to Doxorubicin (Table 1), while no significant differences in sensitivity to 5-Fluorouracil or Carboplatin were observed for DU145RD or 22Rv1RD in comparison to their respective parent cells
Docetaxel-resistant Variants do not Differ in Morphology but have Different Proliferation, Motility and Invasion Phenotypes Versus Parent Cell Lines
Summary
While docetaxel offers improvement in overall survival for patients with hormone-refractory prostate cancer (HRPC) as evident from two Phase III trials (TAX 327 and SWOG 9916) and subsequent clinical management, relapse is almost inevitable. Recent studies suggest that phenotypic changes associated with cancer may be transferred from cell-to-cell via microvesicles/exosomes. Exosomes have been described as nanosized membrane-bound vesicles of endocytic origin [8] Depending on their cell of origin, these small vesicles have been implicated with several different roles some of which include their association with diseased states such as cancer. Hormone-refractory prostate cancer remains hindered by inevitable progression of resistance to first-line treatment with docetaxel. We aimed to investigate phenotypic changes associated with docetaxelresistance in order to help determine the complexity of this problem and to assess the relevance of secreted exosomes in prostate cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
