Moderate stem-cell telomere shortening rate postpones cancer onset in a stochastic model.
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.
University of Copenhagen, Niels Bohr Institute, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.
Simon
S
Holbek
Kristian Moss
KM
Bendtsen
Jeppe
J
Juul
D000375:Aging / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism*; D013269:Stochastic Processes; D016615:Telomere / Q000235:genetics; D059506:Telomere Shortening