Cancer reversion with oocyte extracts is mediated by cell cycle arrest and induction of tumour dormancy.
Cancer reversion with oocyte extracts is mediated by cell cycle arrest and induction of tumour dormancy.
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DOI：
10.18632/oncotarget.24664
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发表时间：
2018-03-23
期刊：
影响因子：
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通讯作者：
Allegrucci C
中科院分区：
文献类型：
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作者：
Saad N;Alberio R;Johnson AD;Emes RD;Giles TC;Clarke P;Grabowska AM;Allegrucci C
当癌症无法根除时，通过肿瘤逆转来稳定控制肿瘤生长是癌症治疗的一种替代方法。这一过程需要重新建立在癌细胞中丢失的正常控制机制，以便能够阻止异常增殖。胚胎环境可以重置细胞程序，我们之前已经证明，Axolotl卵母细胞提取物可以重新编程乳腺癌细胞，并逆转其致瘤性。在这项研究中，我们分析了经卵母细胞提取液处理的异种肿瘤移植瘤的基因表达谱，以表明肿瘤重新编程涉及细胞周期停滞和获得静止状态。肿瘤休眠与P27表达增加、Rb功能恢复和丝裂原激活的信号通路下调有关。我们还表明，静止状态与H4K20me3水平的增加和H4K20me1的减少有关，H4K20me1是导致染色质压缩的表观遗传学特征。卵母细胞提取物诱导的表观遗传重编程是Rb低磷酸化和P27表达诱导所必需的，两者都发生在暴露于卵母细胞提取物的过程中，并稳定地维持在重编程的肿瘤移植瘤中。因此，本研究证明了卵母细胞分子在诱导肿瘤逆转和开发基于化疗镇静的新疗法方面的价值。
Inducing stable control of tumour growth by tumour reversion is an alternative approach to cancer treatment when eradication of the disease cannot be achieved. The process requires re-establishment of normal control mechanisms that are lost in cancer cells so that abnormal proliferation can be halted. Embryonic environments can reset cellular programmes and we previously showed that axolotl oocyte extracts can reprogram breast cancer cells and reverse their tumorigenicity. In this study, we analysed the gene expression profiles of oocyte extract-treated tumour xenografts to show that tumour reprogramming involves cell cycle arrest and acquisition of a quiescent state. Tumour dormancy is associated with increased P27 expression, restoration of RB function and downregulation of mitogen-activated signalling pathways. We also show that the quiescent state is associated with increased levels of H4K20me3 and decreased H4K20me1, an epigenetic profile leading to chromatin compaction. The epigenetic reprogramming induced by oocyte extracts is required for RB hypophosphorylation and induction of P27 expression, both occurring during exposure to the extracts and stably maintained in reprogrammed tumour xenografts. Therefore, this study demonstrates the value of oocyte molecules for inducing tumour reversion and for the development of new chemoquiescence-based therapies.