Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Cardiovasc Res. 2019 Apr 15;115(5):949-959. doi: 10.1093/cvr/cvz024.
Treatment of cancer has evolved in the last decade with the introduction of new therapies. Despite these successes, the lingering cardiotoxic side-effects from chemotherapy remain a major cause of morbidity and mortality in cancer survivors. These effects can develop acutely during treatment, or even years later. Although many risk factors can be identified prior to beginning therapy, unexpected toxicity still occurs, often with lasting consequences. Specifically, cardiotoxicity results in cardiac cell death, eventually leading to cardiomyopathy and heart failure. Certain risk factors may predispose an individual to experiencing adverse cardiovascular effects, and when unexpected cardiotoxicity occurs, it is generally managed with supportive care. Animal models of chemotherapy-induced cardiotoxicity have provided some mechanistic insights, but the precise mechanisms by which these drugs affect the heart remains unknown. Moreover, the genetic rationale as to why some patients are more susceptible to developing cardiotoxicity has yet to be determined. Many genome-wide association studies have identified genomic variants that could be associated with chemotherapy-induced cardiotoxicity, but the lack of validation has made these studies more speculative rather than definitive. With the advent of human induced pluripotent stem cell (iPSC) technology, researchers not only have the opportunity to model human diseases, but also to screen drugs for their efficacy and toxicity using human cell models. Furthermore, it allows us to conduct validation studies to confirm the role of genomic variants in human diseases. In this review, we discuss the role of iPSCs in modelling chemotherapy-induced cardiotoxicity.
在过去的十年中,随着新疗法的引入,癌症治疗取得了进展。尽管取得了这些成功,但化疗引起的持续存在的心脏毒性副作用仍然是癌症幸存者发病率和死亡率的主要原因。这些影响可能在治疗期间急性发展,甚至在几年后发生。尽管在开始治疗前可以识别许多风险因素,但仍会出现意外的毒性,通常会产生持久的后果。具体而言,心脏毒性导致心肌细胞死亡,最终导致心肌病和心力衰竭。某些危险因素可能使个体易患不良心血管影响,并且当发生意外的心脏毒性时,通常通过支持性护理进行管理。化疗诱导的心脏毒性的动物模型提供了一些机制见解,但这些药物影响心脏的确切机制尚不清楚。此外,为什么有些患者更容易发生心脏毒性的遗传依据尚未确定。许多全基因组关联研究已经确定了与化疗诱导的心脏毒性相关的基因组变异,但缺乏验证使得这些研究更具推测性而非确定性。随着人类诱导多能干细胞(iPSC)技术的出现,研究人员不仅有机会对人类疾病进行建模,还可以使用人类细胞模型对药物的功效和毒性进行筛选。此外,它还使我们能够进行验证研究,以确认基因组变异在人类疾病中的作用。在这篇综述中,我们讨论了 iPSC 在模拟化疗诱导的心脏毒性中的作用。