(A)Symmetric Stem Cell Replication and Cancer

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Abstract
Most tissues in metazoans undergo continuous turnover due to cell death or epithelial shedding. Since cellular replication is associated with an inherent risk of mutagenesis, tissues are maintained by a small group of stem cells (SCs) that replicate slowly to maintain their own population and that give rise to differentiated cells. There is increasing evidence that many tumors are also maintained by a small population of cancer stem cells that may arise by mutations from normal SCs. SC replication can be either symmetric or asymmetric. The former can lead to expansion of the SC pool. We describe a simple model to evaluate the impact of (a)symmetric SC replication on the expansion of mutant SCs and to show that mutations that increase the probability of asymmetric replication can lead to rapid mutant SC expansion in the absence of a selective fitness advantage. Mutations in several genes can lead to this process and may be at the root of the carcinogenic process. In multicellular organisms, tissues such as skin, the gut, and blood undergo continuous cell turnover. These tissues are maintained by a small group of tightly regulated cells known as stem cells (SCs) that have two defining properties: they can renew themselves and give rise to more specialized cells that perform tissue specific tasks. Somatic SCs live for many years and replicate slowly to minimize the risk of acquiring mutations in their DNA. When a SC divides, the two daughter cells may have similar properties (symmetric division) or may have different fates (asymmetric division). Symmetric division may allow SCs to expand, and mutations that alter the probability of symmetric versus asymmetric division might increase the risk of tumor growth. This property is important since there is increasing evidence that even tumors have their own SCs. Mutations can transform wild-type SCs into tumor SCs with modified cell division properties, which have decisive impact on cancer progression. Here we develop a mathematical model to illustrate the impact of mutations that regulate the symmetry of SC division on the development of tumors. Our results provide novel insights on the pathway to cancer by mutations within SCs.