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

Abstract

Tumor hypoxia is relevant for tumor growth, metabolism and epithelial-to-mesenchymal transition (EMT). We report that hyperbaric oxygen (HBO) treatment induced mesenchymal-to-epithelial transition (MET) in a dimetyl-α-benzantracene induced mammary rat adenocarcinoma model, and the MET was associated with extensive coordinated gene expression changes and less aggressive tumors. One group of tumor bearing rats was exposed to HBO (2 bar, pO2 = 2 bar, 4 exposures à 90 minutes), whereas the control group was housed under normal atmosphere (1 bar, pO2 = 0.2 bar). Treatment effects were determined by assessment of tumor growth, tumor vascularisation, tumor cell proliferation, cell death, collagen fibrils and gene 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 blood vessels and collagen fibrils, together with an increase in cell death, are consistent with tumor growth reduction and tumor stroma 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 together with a shift towards non-tumorigenic metabolism. This leads to more differentiated and less aggressive tumors, and indicates that oxygen per se might be an important factor in the “switches” of EMT and MET in vivo. HBO treatment also attenuated tumor growth and changed tumor stroma, by targeting the vascular system, having anti-proliferative and pro-apoptotic effects.

Establishment and characterization of a new hypoxia-resistant cancer cell line, OCUM-12/Hypo, derived from a scirrhous gastric carcinoma

“…The mRNA expression levels of Snail-1, Slug/Snail-2, Twist, ZEB-1, ZEB-2 were higher in OCUM-12/Hypo cells in comparison with the OCUM-12 cells. Several transcription factors have been associated with the repression of E-cadherin, including the Snail-1, Slug/Snail-2, Twist, ZEB-1, and ZEB-2 (Imai et al, 2003;Moen et al, 2009). These findings may show that hypoxia induces downregulation of E-cadherin in gastric carcinoma cells, through upregulation of the transcriptional repressor Snail, Twist, and ZEB families.…”

“…However, the serial passages were carried out quickly in a few minutes, and OCUM-12/Hypo cells were returned to 1% O 2 immediately. Moen et al (2009) indicated that hyperoxia treatment for 90 min might cause the mesenchymal-toepithelial transition 'switches' in vivo. In contrast, no morphologic change was found during the serial passages, because our serial passages were carried out for only a few minutes.…”

Mechanism of the Mesenchymal–Epithelial Transition and Its Relationship with Metastatic Tumor Formation

“…Downregulation of Notch signaling by siRNA also led to partial reversal of the EMT phenotype and decreased expression of vimentin, ZEB1, Slug, Snail, and NF-kB (67). Furthermore, Snai1 and Twist2 were also significantly downregulated during MET-induced hyperbaric oxygen treatment in a 7,12 dimethylbenz(a)anthracene (DMBA)-induced mammary rat adenocarcinoma model (68). All of these findings suggest that these transcription factors are closely associated with MET.…”

Inhibition of ZNF746 suppresses invasion and epithelial to mesenchymal transition in H460 non-small cell lung cancer cells

“…Hypoxia plays an important role in the progression and metastasis of cancer (31). Also, hypoxia inducible factor (HIF) α regulates transcriptional regulators of EMT such as Twist (32)and ZEB1 (33)(34)(35).…”