Menendez Javier A, Alarcón Tomás
Metabolism and Cancer Group, Program Against Cancer Therapeutic Resistance, Catalan Institute of OncologyGirona, Spain.
Molecular Oncology Group, Girona Biomedical Research Institute (IDIBGI)Girona, Spain.
Front Cell Dev Biol. 2017 May 5;5:49. doi: 10.3389/fcell.2017.00049. eCollection 2017.
The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate reprogramming cycles of tissue repair outlines a threshold model of aging and cancer. The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current deterministic genetic paradigm for most chronic diseases, thereby increasing the spectrum of therapeutic approaches for physiological aging and cancer.
成体组织无法短暂地生成具有功能性干细胞样特性的细胞是组织自我修复的主要障碍。诱导表观遗传可塑性和表型可塑性短暂获得的核重编程样现象可能构成人类组织对损伤、应激和疾病作出反应的修复途径。然而，组织年轻化不仅应涉及分化细胞的短暂表观遗传重编程，还应涉及对原始或替代终末细胞命运的定向重新获得。慢性或不受控制的表观遗传可塑性会通过损害受损细胞的修复或替代而驱动衰老表型；这种不受控制的重编程现象也可能产生类癌细胞状态。我们在此提出，衰老相关炎症信号调节组织修复重编程周期的能力勾勒出衰老和癌症的阈值模型。衰老/炎症相关偏离稳态的程度可能描绘出一种阈值算法，以区分重编程的有益和有害影响。首先，NF-κB相关先天免疫和衰老相关炎症成分（如IL-6）的短暂激活可能促进对急性炎症事件的修复性细胞重编程。其次，旁炎症转换可能促进对修复性细胞重编程的持久但可逆的不应性。第三，慢性衰老相关炎症信号可能将细胞锁定在高度可塑性的表观遗传状态，使其无法进行修复性分化。将以细胞重编程为中心的表观遗传可塑性观点视为组织成功修复、衰老退化或恶性转化能力的基本要素，应该为当前大多数慢性疾病的确定性遗传范式提供具有挑战性的随机见解，从而增加针对生理性衰老和癌症的治疗方法的范围。
