Abstract
BackgroundThe evolutionary dynamics between interacting heterogeneous cell types are fundamental properties of neoplastic progression but can be difficult to measure and quantify. Cancers are heterogeneous mixtures of mutant clones but the direct effect of interactions between these clones is rarely documented. The implicit goal of most preventive interventions is to bias competition in favor of normal cells over neoplastic cells. However, this is rarely explicitly tested. Here we have developed a cell culture competition model to allow for direct observation of the effect of chemopreventive or therapeutic agents on two interacting cell types. We have examined competition between normal and Barrett's esophagus cell lines, in the hopes of identifying a system that could screen for potential chemopreventive agents.MethodsOne fluorescently-labeled normal squamous esophageal cell line (EPC2-hTERT) was grown in competition with one of four Barrett's esophagus cell lines (CP-A, CP-B, CP-C, CP-D) under varying conditions and the outcome of competition measured over 14 days by flow cytometry.ResultsWe demonstrate that ascorbic acid (vitamin C) can help squamous cells outcompete Barrett's cells in this system. We are also able to show that ascorbic acid's boost to the relative fitness of squamous cells was increased in most cases by mimicking the pH conditions of gastrointestinal reflux in the lower esophagus.ConclusionsThis model is able to integrate differential fitness effects on various cell types, allowing us to simultaneously capture effects on interacting cell types without having to perform separate experiments. This model system may be used to screen for new classes of cancer prevention agents designed to modulate the competition between normal and neoplastic cells.
Highlights
The evolutionary dynamics between interacting heterogeneous cell types are fundamental properties of neoplastic progression but can be difficult to measure and quantify
We have developed a sensitive in vitro model of competition between Barrett’s esophagus and squamous esophageal cells that may be used to identify a new class of interventions, explicitly designed to modulate competition in favor of normal cells
While we find that squamous cells more rapidly outcompete Barrett’s esophagus (BE) cells in the presence of vitamin C, this effect is often not dosedependent
Summary
The evolutionary dynamics between interacting heterogeneous cell types are fundamental properties of neoplastic progression but can be difficult to measure and quantify. We have developed a cell culture competition model to allow for direct observation of the effect of chemopreventive or therapeutic agents on two interacting cell types. 2) the “normal” cells may gain a competitive advantage from a mitogen or survival factor added to the neoplastic environment that differentially affects cell fitness, allowing the normal cells to outcompete the neoplastic cells, a strategy we refer to as “benign cell boosters” [2]. Computational models suggest this may be an effective strategy to harness clonal competition to prevent cancer [2]
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