Mahon K L, Lin H-M, Castillo L, Lee B Y, Lee-Ng M, Chatfield M D, Chiam K, Breit S N, Brown D A, Molloy M P, Marx G M, Pavlakis N, Boyer M J, Stockler M R, Daly R J, Henshall S M, Horvath L G
1] Chris O'Brien Lifehouse, Missenden Road, Camperdown, NSW 2050, Australia [2] Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia [3] University of Sydney, Sydney, New South Wales 2050, Australia.
Cancer Research Division, Garvan Institute of Medical Research/The Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
Br J Cancer. 2015 Apr 14;112(8):1340-8. doi: 10.1038/bjc.2015.74. Epub 2015 Mar 31.
Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort.
PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response.
PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002).
In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.
多西他赛可改善转移性去势抵抗性前列腺癌（CRPC）的症状并延长生存期。然而，约50%的患者存在化疗耐药。本研究探讨细胞因子水平的变化是否能在体外和临床队列中预测多西他赛耐药。
将PC3细胞或其多西他赛耐药亚系（PC3Rx）与U937单核细胞共培养，有无多西他赛处理，然后检测细胞因子水平。对55例CRPC男性患者在多西他赛第1周期前后检测28种细胞因子的循环水平，并与前列腺特异性抗原（PSA）反应进行比较。
与PC3-U937共培养相比，PC3Rx-U937共培养表达更多细胞因子，主要是替代性巨噬细胞分化标志物。多西他赛处理增强了PC3Rx-U937共培养的细胞因子产生，同时降低了PC3-U937中的细胞因子水平。在患者中，多西他赛第1周期后七种循环细胞因子（巨噬细胞抑制细胞因子1（MIC1）、白细胞介素（IL）-1ra、IL-1β、IL-4、IL-6、IL-12和IFNγ）水平的变化与疾病进展相关（所有P<0.05）。MIC1、IL-4和IL-6变化的组合对PSA反应的预测最强（P=0.002）。
体外研究表明，多西他赛耐药至少部分是由多西他赛耐药肿瘤细胞与巨噬细胞相互作用诱导的细胞因子介导的。循环细胞因子水平的早期变化与CRPC患者的多西他赛耐药相关。综合来看，这些数据表明炎症反应和巨噬细胞在CRPC多西他赛耐药的发生中起重要作用。
