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

TLDR

Colorectal cancer originates in colonic crypts, where successive genetic or epigenetic changes can disrupt homeostasis and drive unbounded growth. The study aims to model the dynamics of a single colorectal crypt using a compartmental approach that incorporates stem, differentiated, and transit cell populations. The authors extend the Tomlinson–Bodmer model by relaxing synchronous division assumptions, adopting an age‑structured, continuum framework, and exploring two regulatory mechanisms that can sustain equilibrium or permit unbounded proliferation. The first mechanism always stabilizes equilibrium across all parameter values, while the second permits unbounded growth when net per‑capita rates are high, explaining how increased cell renewal can drive cancer and accounting for long lag phases before unlimited proliferation.

Abstract

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: 11130–11134 ], 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.