Abstract
Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.
Full Text
The Full Text of this article is available as a PDF (92.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bach S. P., Renehan A. G., Potten C. S. Stem cells: the intestinal stem cell as a paradigm. Carcinogenesis. 2000 Mar;21(3):469–476. doi: 10.1093/carcin/21.3.469. [DOI] [PubMed] [Google Scholar]
- Cairns J. Mutation selection and the natural history of cancer. Nature. 1975 May 15;255(5505):197–200. doi: 10.1038/255197a0. [DOI] [PubMed] [Google Scholar]
- Cairns John. Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci U S A. 2002 Jul 29;99(16):10567–10570. doi: 10.1073/pnas.162369899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hanahan D., Weinberg R. A. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57–70. doi: 10.1016/s0092-8674(00)81683-9. [DOI] [PubMed] [Google Scholar]
- Janes Sam M., Lowell Sally, Hutter Caroline. Epidermal stem cells. J Pathol. 2002 Jul;197(4):479–491. doi: 10.1002/path.1156. [DOI] [PubMed] [Google Scholar]
- Knudson A. G. Antioncogenes and human cancer. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10914–10921. doi: 10.1073/pnas.90.23.10914. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nunney L. Lineage selection and the evolution of multistage carcinogenesis. Proc Biol Sci. 1999 Mar 7;266(1418):493–498. doi: 10.1098/rspb.1999.0664. [DOI] [PMC free article] [PubMed] [Google Scholar]