Holbek Simon, Bendtsen Kristian Moss, Juul Jeppe
University of Copenhagen, Niels Bohr Institute, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.
Phys Rev E Stat Nonlin Soft Matter Phys. 2013 Oct;88(4):042706. doi: 10.1103/PhysRevE.88.042706. Epub 2013 Oct 21.
Mammalian cells are restricted from proliferating indefinitely. Telomeres at the end of each chromosome are shortened at cell division and when they reach a critical length, the cell will enter permanent cell cycle arrest-a state known as senescence. This mechanism is thought to be tumor suppressing, as it helps prevent precancerous cells from dividing uncontrollably. Stem cells express the enzyme telomerase, which elongates the telomeres, thereby postponing senescence. However, unlike germ cells and most types of cancer cells, stem cells only express telomerase at levels insufficient to fully maintain the length of their telomeres, leading to a slow decline in proliferation potential. It is not yet fully understood how this decline influences the risk of cancer and the longevity of the organism. We here develop a stochastic model to explore the role of telomere dynamics in relation to both senescence and cancer. The model describes the accumulation of cancerous mutations in a multicellular organism and creates a coherent theoretical framework for interpreting the results of several recent experiments on telomerase regulation. We demonstrate that the longest average cancer-free lifespan before cancer onset is obtained when stem cells start with relatively long telomeres that are shortened at a steady rate at cell division. Furthermore, the risk of cancer early in life can be reduced by having a short initial telomere length. Finally, our model suggests that evolution will favor a shorter than optimal average cancer-free lifespan in order to postpone cancer onset until late in life.
哺乳动物细胞的增殖受到限制，无法无限期进行。每条染色体末端的端粒在细胞分裂时会缩短，当端粒长度达到临界值时，细胞将进入永久性细胞周期停滞状态，即衰老状态。这种机制被认为具有肿瘤抑制作用，因为它有助于防止癌前细胞不受控制地分裂。干细胞表达端粒酶，该酶可延长端粒，从而延缓衰老。然而，与生殖细胞和大多数癌细胞不同，干细胞仅以不足以完全维持其端粒长度的水平表达端粒酶，导致其增殖潜能缓慢下降。目前尚不完全清楚这种下降如何影响癌症风险和生物体的寿命。我们在此开发了一个随机模型，以探讨端粒动态变化在衰老和癌症方面的作用。该模型描述了多细胞生物中癌性突变的积累，并为解释最近几项关于端粒酶调控的实验结果创建了一个连贯的理论框架。我们证明，当干细胞起始端粒相对较长且在细胞分裂时以稳定速率缩短时，在癌症发生前可获得最长的平均无癌寿命。此外，初始端粒长度较短可降低生命早期患癌的风险。最后，我们的模型表明，进化将倾向于一个比最优平均无癌寿命更短的寿命，以便将癌症发生推迟到生命后期。
