Hyperoxic Treatment Induces Mesenchymal-to-Epithelial Transition in a Rat Adenocarcinoma Model

AbstractTumor hypoxia is relevant for tumor growth, metabolism and epithelial-to-mesenchymal transition (EMT). We report thathyperbaric oxygen (HBO) treatment induced mesenchymal-to-epithelial transition (MET) in a dimetyl-a-benzantraceneinduced mammary rat adenocarcinoma model, and the MET was associated with extensive coordinated gene expressionchanges and less aggressive tumors. One group of tumor bearing rats was exposed to HBO (2 bar, pO2 = 2 bar, 4 exposures a`90 minutes), whereas the control group was housed under normal atmosphere (1 bar, pO2 = 0.2 bar). Treatment effects weredetermined by assessment of tumor growth, tumor vascularisation, tumor cell proliferation, cell death, collagen fibrils andgene expression profile. Tumor growth was significantly reduced (,16%) after HBO treatment compared to day 1 levels,whereas control tumors increased almost 100% in volume. Significant decreases in tumor cell proliferation, tumor bloodvessels and collagen fibrils, together with an increase in cell death, are consistent with tumor growth reduction and tumorstroma influence after hyperoxic treatment. Gene expression profiling showed that HBO induced MET. In conclusion,hyperoxia induced MET with coordinated expression of gene modules involved in cell junctions and attachments togetherwith a shift towards non-tumorigenic metabolism. This leads to more differentiated and less aggressive tumors, andindicates that oxygen per se might be an important factor in the ‘‘switches’’ of EMT and MET in vivo. HBO treatment alsoattenuated tumor growth and changed tumor stroma, by targeting the vascular system, having anti-proliferative and pro apoptotic effects.