Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida.
Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Transl Res. 2015 Jan;165(1):241-9. doi: 10.1016/j.trsl.2014.05.007. Epub 2014 May 21.
Epigenetic states can govern the plasticity of a genome to be adaptive to environments where many stress stimuli and insults compromise the homeostatic system with age. Although certain elastic power may autonomously reset, reprogram, rejuvenate, or reverse the organismal aging process, enforced genetic manipulations could at least reset and reprogram epigenetic states beyond phenotypic plasticity and elasticity in cells, which can be further manipulated into organisms. The question, however, remains how we can rejuvenate intrinsic resources and infrastructures in a noninvasive manner, particularly in a whole complex aging organism. Given inevitable increase of cancer with age, presumably any failure of resetting, reprogramming, or even rejuvenation could be a prominent causative factor of malignancy. Accompanied by progressive deteriorations of physiological functions in organisms with advancing age, aging-associated cancer risk may essentially arise from unforeseen complications in cellular senescence. At the cellular level, epithelial-mesenchymal plasticity (dynamic and reversible transitions between epithelial and mesenchymal phenotypic states) is enabled by underlying shifts in epigenetic regulation. Thus, the epithelial-mesenchymal transition (EMT) and its reversal (mesenchymal-epithelial transition [MET]) function as a key of cellular transdifferentiation programs. On the one hand, the EMT-MET process was initially appreciated in developmental biology, but is now attracting increasing attention in oncogenesis and senescence, because the process is involved in the malignant progression vs regression of cancer. On the other hand, senescence is often considered the antithesis of early development, but yet between these 2 phenomena, there may be common factors and governing mechanisms such as the EMT-MET program, to steer toward rejuvenation of the biological aging system, thereby precisely controlling or avoiding cancer through epigenetic interventions.
表观遗传状态可以控制基因组的可塑性，使其适应环境。在这个环境中，许多应激刺激和损伤会随着年龄的增长而损害内稳态系统。尽管某些弹性可能会自主重置、重新编程、恢复活力或逆转机体衰老过程，但强制的遗传操作至少可以重置和重新编程细胞中的表观遗传状态，超越表型可塑性和弹性，进一步将细胞操纵为生物体。然而，问题仍然是我们如何以非侵入性的方式恢复内在资源和基础设施，特别是在整个复杂的衰老生物体中。考虑到癌症随着年龄的增长而必然增加，重置、重新编程甚至恢复活力的任何失败都可能是恶性肿瘤的一个突出致病因素。随着生物体年龄的增长，生理功能逐渐恶化，与衰老相关的癌症风险可能本质上源于细胞衰老过程中不可预见的并发症。在细胞水平上，上皮-间充质可塑性（上皮和间充质表型状态之间的动态和可逆转变）是由表观遗传调控的潜在变化所允许的。因此，上皮-间充质转化（EMT）及其逆转（间充质-上皮转化[MET]）作为细胞转分化程序的关键。一方面，EMT-MET 过程最初在发育生物学中得到了认识，但现在在肿瘤发生和衰老中越来越受到关注，因为该过程涉及癌症的恶性进展与消退。另一方面，衰老通常被认为是早期发育的对立面，但在这两种现象之间，可能存在共同的因素和调控机制，如 EMT-MET 程序，以推动生物衰老系统的恢复活力，从而通过表观遗传干预精确控制或避免癌症。
