Abstract
BackgroundThree-dimensional (3D) embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer. Although these are orders of magnitude simpler than tissues, they too are complex systems that have proven challenging to understand. We used agent-based, discrete event simulation modeling methods to build working hypotheses of mechanisms of epithelial 3D culture phenotype and early cancer progression. Starting with an earlier software analogue, we validated an improved in silico epithelial analogue (ISEA) for cardinal features of a normally developed MDCK cyst. A set of axiomatic operating principles defined simulated cell actions. We explored selective disruption of individual simulated cell actions. New framework features enabled recording detailed measures of ISEA cell activities and morphology.ResultsEnabled by a small set of cell operating principles, ISEA cells multiplied and self-organized into cyst-like structures that mimicked those of MDCK cells in a 3D embedded cell culture. Selective disruption of "anoikis" or directional cell division caused the ISEA to develop phenotypic features resembling those of in vitro tumor reconstruction models and cancerous tissues in vivo. Disrupting either process, or both, altered cell activity patterns that resulted in morphologically similar outcomes. Increased disruption led to a prolonged presence of intraluminal cells.ConclusionsISEA mechanisms, behaviors, and morphological properties may have biological counterparts. To the extent that in silico-to-in vitro mappings are valid, the results suggest plausible, additional mechanisms of in vitro cancer reconstruction or reversion, and raise potentially significant implications for early cancer diagnosis based on histology. Further ISEA development and use are expected to provide a viable platform to complement in vitro methods for unraveling the mechanistic basis of epithelial morphogenesis and cancer progression.
Highlights
Three-dimensional (3D) embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer
What level of deregulation is required before the histology becomes abnormal? Can a mechanism of deregulation be inferred from the abnormal phenotype? To better understand causal linkages between mechanisms and phenotype in an in vitro setting, epithelial cells have been cultured and studied in three-dimensional (3D) gels of extracellular matrix (ECM), such as collagen I or Matrigel®
We suggest that progress can be made in understanding epithelial cell behavior, morphology, and mechanisms, along with the changes that occur during cancer progression by constructing and studying abstract analogues in software, where the system features at all levels can be modeled, fully explored, and understood
Summary
Three-dimensional (3D) embedded cell cultures provide an appropriate physiological environment to reconstruct features of early glandular epithelial cancer. These are orders of magnitude simpler than tissues, they too are complex systems that have proven challenging to understand. When manipulated or exposed to certain factors, the organoids and composing cells exhibit phenotypic features that are associated with pre-cancerous or cancerous tissues in vivo [3]. Such cell culture models are thought to provide an appropriate physiological environment to study glandular epithelial morphogenesis and cancer progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
