Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodm...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-03, Vol.104 (10), p.4008-4013
Main Authors: Johnston, Matthew D, Edwards, Carina M, Bodmer, Walter F, Maini, Philip K, Chapman, S. Jonathan
Format: Article
Language:English
Subjects:
Biological Sciences
Cell cycle
Cell Differentiation
Cell division
Cell growth
Cell Transformation, Neoplastic
Cellular differentiation
Colon - pathology
Colon - physiology
Colorectal cancer
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Crypts
Feedback, Physiological
Genetic mutation
Genetics
Homeostasis
Humans
Mathematical models
Models, Biological
Models, Statistical
Models, Theoretical
Mutation
Oncology
Parametric models
Physical Sciences
Population growth
Stem cells
Stem Cells - cytology
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Summary:Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodmer WF (1995) Proc Natl Acad Sci USA 92:], which accounts for populations of stem cells, differentiated cells, and transit cells. That original model made the simplifying assumptions that each cell population divides synchronously, but we relax these assumptions by adopting an age-structured approach that models asynchronous cell division, and by using a continuum model. We discuss two mechanisms that could regulate the growth of cell numbers and maintain the equilibrium that is normally observed in the crypt. The first will always maintain an equilibrium for all parameter values, whereas the second can allow unbounded proliferation if the net per capita growth rates are large enough. Results show that an increase in cell renewal, which is equivalent to a failure of programmed cell death or of differentiation, can lead to the growth of cancers. The second model can be used to explain the long lag phases in tumor growth, during which new, higher equilibria are reached, before unlimited growth in cell numbers ensues.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0611179104