6th ESACP Congress, Heidelberg, April 7-11, 1999

A105
COMPUTER MODEL TO SIMULATE EPITHELIAL HOMEOSTASIS AND TUMOR GENESIS
Morel D, Marcelpoil R, Brugal G

Equipe RFMQ - Laboratoire TIMC / IMAG Institut Albert Bonniot Faculté de Médecine, La Tronche CEDEX, France

The mechanisms controlling the homeostasis in a normal stratified epithelium are still not clear in vivo though many of them are now well characterized in vitro. Neither are the modifications of these controls misleading cells into a pathological behavior. Computer simulation represents a powerful tool to investigate the field of cell proliferation control in vivo, to test hypotheses and to observe their consequences in a time dependent context. Our approach is a first step in the application of the concept of "dynamic cellular sociology". It associates a spatial representation of cells using the Voronoi graph and a behavioral model of cell proliferation controls. The Voronoi graph associates a polygon to every cell, the set of these polygons defines the tissue architecture. The behavioral model for cell proliferation includes intracellular (cyclins, Cyclin-dependent kinases, Rb, Cdks Inhibitors) and extracellular (growth and differentiation factors, integrins...) controls. We will show how the proposed model integrating the spatial representation of cells permits a quantitative modulation of the extracellular signals as a function of the cell neighborhood during time dependent simulations. Our first results concern the homeostasis of stratified epithelia (epidermis and cornea). They illustrate the influence of the microenvironment and the patterning of stem cells on cell proliferation in basal layers ("niche" hypothesis). Simulations will soon be validated using cell cycle status derived from proliferation markers quantification and microscopy images of tissue section from normal and malignant specimens. Future work will aim at studying the diversity of unbalanced regulation mechanisms that lead to pathogenesis.