Differential platelet levels affect response to taxane-based therapy in ovarian cancer.
Differential platelet levels affect response to taxane-based therapy in ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-14-0870
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发表时间：
2015-02-01
期刊：
影响因子：
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通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Bottsford-Miller J;Choi HJ;Dalton HJ;Stone RL;Cho MS;Haemmerle M;Nick AM;Pradeep S;Zand B;Previs RA;Pecot CV;Crane EK;Hu W;Lutgendorf SK;Afshar-Kharghan V;Sood AK
我们假设治疗期间的血小板水平可以作为治疗反应的生物标志物，并且血小板水平的操纵可以影响对化疗的反应性。回顾性查询复发性或进展性卵巢癌患者的病历，了解其在初次治疗期间血小板和CA-125水平的变化。使用体外共培养实验和小鼠中人卵巢癌的体内原位模型来测试调节血小板水平对肿瘤生长和对多西他赛的反应性的影响。诊断卵巢癌时的血小板增多与进展间隔时间缩短（p = 0.05）和中位总生存期缩短（p = 0.007）相关。平均血小板水平在初次治疗期间得到纠正，复发时升高。与治疗应答患者相反，在一组对主要治疗难治的患者中，血小板水平在治疗期间未恢复正常。在A2780、HeyA 8和SKOV 3-ip 1卵巢癌细胞系中，血小板共培养保护免于凋亡（p < 0.05）。在人卵巢癌的原位模型中，血小板耗竭导致平均肿瘤重量减少70%（p < 0.05）。与用多西他赛处理的小鼠相比，用多西他赛和血小板消耗抗体处理的小鼠的平均肿瘤重量降低62%（p = 0.04）。血小板输注使平均聚集肿瘤重量增加了2.4倍（p < 0.05），阻断了多西他赛对肿瘤生长的作用（p = 0.55），并减少了肿瘤细胞凋亡。输血前血小板的阿司匹林化阻断了输血的促生长作用。化疗反应的血小板驱动效应可以解释临床观察结果。
We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro co-culture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. Thrombocytosis at the diagnosis of ovarian cancer correlated with decreased interval to progression (p = 0.05) and median overall survival (p = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet co-culture protected against apoptosis (p < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (p < 0.05). Compared to mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (p = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (p < 0.05), blocked the effect of docetaxel on tumor growth (p = 0.55) and decreased tumor cell apoptosis. Pre-transfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. Platelet-driven effects of chemotherapy response may explain clinical observations.