title: Quantifying replicative senescence as a tumor suppressor pathway and a target for cancer therapy.
abstract: To study quantitatively replicative senescence as a tumor suppressor mechanism, we investigate the distribution of a growing clonal cell population restricted by Hayflick's limit. We find that in the biologically relevant range of parameters, if the imbalance between cell division and death is moderate or low (high death-to-birth ratio), senescence offers significant protection against cancer by halting abnormal cell proliferation at early pre-diagnostic stages of tumor development. We also find that by the time tumors are typically detected, there is a high probability that telomerase is activated, even if the cell of origin was telomerase negative. Hence, the fact that most cancers are positive for telomerase is not necessarily an indication that cancer originated in a telomerase positive cell. Finally, we discuss how the population dynamics of cells can determine the outcomes of anti-telomerase cancer therapies, and provide guidelines on how the model could potentially be applied to develop clinically useful tools to predict the response to treatment by telomerase inhibitors in individual patients.
authors.affiliation: Department of Mathematics, Univeristy of California, Irvine, U.S.A.|Department of Ecology and Evolution, Univeristy of California, Irvine, U.S.A.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Rodriguez-Brenes
authors.affiliation: Department of Mathematics, Univeristy of California, Irvine, U.S.A.|Department of Ecology and Evolution, Univeristy of California, Irvine, U.S.A.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wodarz
authors.affiliation: Department of Mathematics, Univeristy of California, Irvine, U.S.A.|Department of Ecology and Evolution, Univeristy of California, Irvine, U.S.A.
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Komarova
mesh_terms: D000465:Algorithms; D016922:Cellular Senescence / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D019098:Telomerase