Catalan Institute of Oncology, Girona, Catalonia, Spain.
Rejuvenation Res. 2010 Oct;13(5):519-26. doi: 10.1089/rej.2010.1022. Epub 2010 Nov 3.
Networks of oncogenes and tumor suppressor genes that control cancer cell proliferation also regulate stem cell renewal and possibly stem cell aging. Because (de)differentiation processes might dictate tumor cells to retrogress to a more stem-like state in response to aging-relevant epigenetic and/or environmental players, we recently envisioned that cultured human cancer cells might be used as reliable models to test the ability of antiaging interventions for promoting the initiation and maintenance of self-renewing divisions. Cancer cell lines naturally bearing undetectable amounts of stem/progenitor-like cell populations were continuously cultured in the presence of the caloric restriction mimetic metformin for several months. Microarray technology was employed to profile expression of genes related to the identification, growth, and differentiation of stem cells. Detection of functionally related gene groups using a pathway analysis package provided annotated genetic signatures over- and underexpressed in response to pharmacological mimicking of caloric restriction. By following this methodological approach, we recently obtained data fitting a model in which, in response to chronic impairment of cellular bioenergetics imposed by metformin-induced mitochondrial uncoupling as assessed by the phosphorylation state of cAMP-response element binding protein (CREB), tumor cells can retrogress from a differentiated state to a more CD44(+) stem-like primitive state epigenetically governed by the Polycomb-group suppressor BMI1-a crucial "stemness" gene involved in the epigenetic maintenance of adult stem cells. These findings might provide a novel molecular avenue to investigate if antiaging benefits from caloric restriction mimetics might relate to their ability to epigenetically reprogram stemness while prolonging the capacity of stem-like cell states to proliferate, differentiate, and replace mature cells in adult aging tissues.
控制癌细胞增殖的癌基因和肿瘤抑制基因网络也调节干细胞更新，并且可能调节干细胞衰老。因为（去）分化过程可能会促使肿瘤细胞在衰老相关的表观遗传和/或环境因素的作用下倒退到更类似于干细胞的状态，我们最近设想，培养的人类癌细胞可以作为可靠的模型，用于测试抗衰老干预措施促进自我更新分裂的起始和维持的能力。自然携带难以检测到的干细胞/祖细胞样细胞群体的癌细胞系在卡路里限制模拟物二甲双胍的存在下连续培养数月。微阵列技术用于分析与干细胞的鉴定、生长和分化相关的基因表达。使用途径分析软件包检测功能相关基因群，提供了对卡路里限制的药理学模拟反应过度和不足表达的注释遗传特征。通过遵循这种方法学方法，我们最近获得的数据拟合了一个模型，其中，在由二甲双胍诱导的线粒体解偶联引起的细胞生物能慢性损伤的情况下（如 cAMP 反应元件结合蛋白（CREB）的磷酸化状态所评估），肿瘤细胞可以从分化状态倒退到更类似于 CD44(+)的干细胞原始状态，这种表观遗传状态由多梳组抑制因子 BMI1 控制，BMI1 是一个关键的“干性”基因，参与成年干细胞的表观遗传维持。这些发现可能提供了一条新的分子途径，以研究卡路里限制模拟物的抗衰老益处是否与其能够通过表观遗传重编程干性同时延长类似于干细胞的细胞状态的增殖、分化和替代成年衰老组织中的成熟细胞的能力有关。
