Abstract:
The development of resistance by tumor cells to various types of therapy is a significant problem that decreases the effectiveness of oncology treatments. For more than two decades, comparative transcriptomic studies of tumor cells with different sensitivities to ionizing radiation and chemotherapeutic agents have been conducted in order to identify the causes and mechanisms underlying this phenomenon. However, the results of such studies have little in common and often contradict each other. We have assumed that a systematic analysis of a large number of such studies will provide new knowledge about the mechanisms of development of therapeutic resistance in tumor cells. Our comparison of 123 differentially expressed gene (DEG) lists published in 98 papers suggests a very low degree of consistency between the study results. Grouping the data by type of genotoxic agent and tumor type did not increase the similarity. The most frequently overexpressed genes were found to be those encoding the transport protein ABCB1 and the antiviral defense protein IFITM1. We put forward a hypothesis that the role played by the overexpression of the latter in the development of resistance may be associated not only with the stimulation of proliferation, but also with the limitation of exosomal communication and, as a result, with a decrease in the bystander effect. Among down regulated DEGs, BNIP3 was observed most frequently. The expression of BNIP3, together with BNIP3L, is often suppressed in cells resistant to non-platinum genotoxic chemotherapeutic agents, whereas it is increased in cells resistant to ionizing radiation. These observations are likely to be mediated by the binary effects of these gene products on survival, and regulation of apoptosis and autophagy. The combined data also show that even such obvious mechanisms as inhibition of apoptosis and increase of proliferation are not universal but show multidirectional changes.
摘要:
肿瘤细胞对各种类型的疗法的抗性的发展是降低肿瘤治疗的有效性的重要问题。二十多年来,已经对对电离辐射和化学治疗剂具有不同敏感性的肿瘤细胞进行了比较转录组学研究,以确定这种现象的原因和机制。然而,这些研究的结果几乎没有共同点,而且往往相互矛盾。我们认为,对大量此类研究的系统分析将提供有关肿瘤细胞治疗抗性发展机制的新知识。我们在98篇论文中发表的123个差异表达基因(DEG)列表的比较表明,研究结果之间的一致性程度非常低。按基因毒性剂的类型和肿瘤类型对数据进行分组并没有增加相似性。发现最常见的过表达基因是编码转运蛋白ABCB1和抗病毒防御蛋白IFITM1的基因。我们提出了一个假设,即后者的过表达在抗性发展中所起的作用可能不仅与增殖的刺激有关,而且由于外泌体交流的限制,因此,旁观者效应的降低。在下调的DEG中,BNIP3被最频繁地观察到。BNIP3与BNIP3L的表达,通常在对非铂基因毒性化学治疗剂具有抗性的细胞中被抑制,而在对电离辐射有抵抗力的细胞中,它增加了。这些观察结果可能是由这些基因产物对生存的二元效应介导的,细胞凋亡和自噬的调控。综合数据还表明,即使抑制凋亡和增加增殖等明显机制也不是普遍的,而是显示出多向变化。