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Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model.

Moen I, Øyan AM, Kalland KH, Tronstad KJ, Akslen LA, Chekenya M, Sakariassen PØ, Reed RK, Stuhr LE - PLoS ONE (2009)

Bottom Line: 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.HBO treatment also attenuated tumor growth and changed tumor stroma, by targeting the vascular system, having anti-proliferative and pro-apoptotic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.

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 dimethyl-alpha-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, pO(2) = 2 bar, 4 exposures à 90 minutes), whereas the control group was housed under normal atmosphere (1 bar, pO(2) = 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 (approximately 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.

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Collagen density.The collagen fibril density is shown in control (A) and hyperbaric oxygen (HBO) treated tumors (B) on cross-section fibrils magnified 50.000 times. Scale bar indicates 0.5 µm. Manually counted collagen fibril density ± SEM (C). **p<0.001 compared to controls.
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pone-0006381-g003: Collagen density.The collagen fibril density is shown in control (A) and hyperbaric oxygen (HBO) treated tumors (B) on cross-section fibrils magnified 50.000 times. Scale bar indicates 0.5 µm. Manually counted collagen fibril density ± SEM (C). **p<0.001 compared to controls.

Mentions: There were pronounced differences in collagen fibril density in tumor stroma between control (n = 5) and HBO treated (n = 4) tumors, as displayed in Figures 3A and B. The manually counted fibril density showed a statistically significant decline in fibril density after HBO treatment (Fig. 3C) (p<0.001). The results are supported by microarray analysis, showing down-regulation of several fibrosis-related genes (Table 2).


Hyperoxic treatment induces mesenchymal-to-epithelial transition in a rat adenocarcinoma model.

Moen I, Øyan AM, Kalland KH, Tronstad KJ, Akslen LA, Chekenya M, Sakariassen PØ, Reed RK, Stuhr LE - PLoS ONE (2009)

Collagen density.The collagen fibril density is shown in control (A) and hyperbaric oxygen (HBO) treated tumors (B) on cross-section fibrils magnified 50.000 times. Scale bar indicates 0.5 µm. Manually counted collagen fibril density ± SEM (C). **p<0.001 compared to controls.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2712688&req=5

pone-0006381-g003: Collagen density.The collagen fibril density is shown in control (A) and hyperbaric oxygen (HBO) treated tumors (B) on cross-section fibrils magnified 50.000 times. Scale bar indicates 0.5 µm. Manually counted collagen fibril density ± SEM (C). **p<0.001 compared to controls.
Mentions: There were pronounced differences in collagen fibril density in tumor stroma between control (n = 5) and HBO treated (n = 4) tumors, as displayed in Figures 3A and B. The manually counted fibril density showed a statistically significant decline in fibril density after HBO treatment (Fig. 3C) (p<0.001). The results are supported by microarray analysis, showing down-regulation of several fibrosis-related genes (Table 2).

Bottom Line: 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.HBO treatment also attenuated tumor growth and changed tumor stroma, by targeting the vascular system, having anti-proliferative and pro-apoptotic effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.

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 dimethyl-alpha-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, pO(2) = 2 bar, 4 exposures à 90 minutes), whereas the control group was housed under normal atmosphere (1 bar, pO(2) = 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 (approximately 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.

Show MeSH
Related in: MedlinePlus