Wróbel Tomasz, Luty Marcin, Catapano Jessica, Karnas Elżbieta, Szczygieł Małgorzata, Piwowarczyk Katarzyna, Ryszawy Damian, Drabik Grażyna, Zuba-Surma Ewa, Siedlar Maciej, Madeja Zbigniew, Elas Martyna, Czyż Jarosław
Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
Stem Cells. 2020 Sep 27;38(12):1544-56. doi: 10.1002/stem.3281.
Combinations of metabolic blockers (incl. fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133 and/or CD44 cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44 "bulk" cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44 SCL cells. However, the CD44 offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44 SCL prostate cells and their "bulk" progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.
代谢阻滞剂（包括非诺贝特）与化疗药物的联合使用会干扰前列腺癌细胞的耐药性。然而，它们对前列腺癌恶性肿瘤中癌症干细胞依赖性微进化的影响仍未得到解决。在此，我们假设多西他赛/非诺贝特联合治疗会促使癌症干细胞选择性扩增，从而影响其后代的微进化。因此，我们采用了体外/体内联合方法来确定这一过程的生物学和治疗后果。在前列腺癌DU145和PC3细胞群体中发现了对多西他赛耐药的CD133和/或CD44癌症干细胞样（SCL）细胞的微小亚群。当用多西他赛预处理时，它们很容易分化为对多西他赛耐药的CD44“主体”细胞，从而解释了耐药细胞谱系的微进化。多西他赛/非诺贝特联合治疗诱导了多核巨细胞和耐药CD44 SCL细胞的产生。然而，多西他赛和多西他赛/非诺贝特处理的SCL的CD44后代对联合治疗仍相对敏感，同时对多西他赛保持增强的耐药性。在没有多西他赛/非诺贝特的情况下，耐药SCL衍生谱系的长期传代导致它们向药物敏感性和侵袭性表型逆向微进化。因此，前列腺肿瘤在体内扩张最初停止后能够从多西他赛/非诺贝特联合应激中恢复。总之，我们证实了非诺贝特在节律性治疗耐药前列腺肿瘤方面的潜力。然而，多西他赛/非诺贝特诱导的超耐药CD44 SCL前列腺细胞及其“主体”后代的选择性扩增促使前列腺肿瘤耐药性的微进化。这一过程可能会限制代谢化疗在前列腺癌治疗中的应用。
