Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.
Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes.
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DOI：
10.1371/journal.pone.0050999
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
O'Driscoll L
中科院分区：
文献类型：
--
作者：
Corcoran C;Rani S;O'Brien K;O'Neill A;Prencipe M;Sheikh R;Webb G;McDermott R;Watson W;Crown J;O'Driscoll L
激素难治性前列腺癌仍然受到多西他赛一线治疗不可避免的耐药进展的阻碍。最近的研究表明，与癌症相关的表型变化可能通过微泡/外泌体从细胞转移到细胞。在这里，我们的目的是研究与紫杉醇耐药相关的表型变化，以帮助确定这个问题的复杂性，并评估分泌的外泌体在前列腺癌中的相关性。建立了DU 145和22 Rv 1的多西他赛耐药变体，并在交叉耐药性、形态学、增殖、运动性、侵袭、失巢凋亡、集落形成、外泌体分泌及其功能相关性方面进行了表征。还对来自相关血清样本的外来体进行了初步分析。获得性紫杉醇耐药赋予交叉耐药性阿霉素和诱导的运动，侵袭，增殖和锚定独立的生长的改变。从DU 145和22 Rv 1耐紫杉醇变体（DU 145 RD和22 Rv 1 RD）排出的外泌体赋予DU 145、22 Rv 1和LNCap细胞对紫杉醇的耐药性，这可能部分归因于外泌体MDR-1/P-gp转移。与来自年龄匹配对照的外泌体相比，来自前列腺癌患者血清的外泌体诱导细胞增殖和侵袭增加。此外，当应用于DU 145和22 Rv 1细胞时，来自经历多西他赛治疗过程的患者的血清的外泌体与来自开始多西他赛治疗之前的相同患者的匹配外泌体相比，显示对多西他赛的细胞应答与患者对多西他赛治疗的应答之间的相关性。我们的研究表明前列腺癌中紫杉醇耐药的复杂性和多面性。此外，我们的体外观察和初步临床研究表明，外泌体可能在前列腺癌中，在细胞-细胞通讯中发挥重要作用，因此可能提供作为包含预测生物标志物和新治疗靶点的载体的潜力。
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.
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