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. 2018 Dec 20;9(1):52-57.
doi: 10.1039/c8ra08472f. eCollection 2018 Dec 19.

Sub-lethal hyperthermia promotes epithelial-to-mesenchymal-like transition of breast cancer cells: implication of the synergy between hyperthermia and chemotherapy

Tae Hee Lee  1 , Jiyoon Bu  2 , Byoung Hyuck Kim  3 , Michael J Poellmann  2 , Seungpyo Hong  2   4 , Sung Hee Hyun  1
Affiliations

Sub-lethal hyperthermia promotes epithelial-to-mesenchymal-like transition of breast cancer cells: implication of the synergy between hyperthermia and chemotherapy

Tae Hee Lee et al. RSC Adv. .

Abstract

Thermotherapy has demonstrated a potential to be an effective non-surgical technique to treat breast cancer. Despite its advantages, including low toxicity and high repeatability, thermotherapy is typically required to be applied in combination with other treatments since the residual tumor cells that survive after hyperthermal treatment often cause recurrence. In this study, we confirmed that breast cancer cells tolerate temperature of up to 47 °C by synthesizing a large amount of heat shock proteins. Further changes in the molecular properties of the heat-exposed cells were investigated using western blotting, quantitative reverse transcription polymerase chain reaction, and immunocytochemistry. We found that low-temperature hyperthermia promoted epithelial-to-mesenchymal-like transition (EMT), as observed by the increased mesenchymal marker expression levels while decreasing epithelial markers. Moreover, cell morphology changed from cobblestone-like to a more spindle-like appearance, in addition to significantly enhanced cell motility upon heat treatment. These results all support that sub-lethal hyperthermal stress induces EMT. In addition, we examined changes in the chemo-sensitivity of the heat-treated cells. Addition of a chemo-drugs caused increased cytotoxicity of the heat-treated cells compared to the cells that were not co-treated with heat. Our study demonstrates that thermotherapy alone may cause undesirable EMT, which could be well overcome through a synergistic effect when applied with chemotherapy.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Effect of sub-lethal hyperthermal stress on cell viability: (a) cell viability depending on exposed temperature; (b) expression of heat shock protein 70 (Hsp70) after heat treatment.
Fig. 2
Fig. 2. Effect of sub-lethal hyperthermal stress on cell morphology and migratory capacity: (a) bright field images and (b) periodic acid Schiff (PAS)-stained images of cells after sub-lethal hyperthermia treatment; (c) and migratory capacity of cells after sub-lethal hyperthermia or TGF-β1 treatment; (d) viability of heat-treated cells after 3 h of incubation.
Fig. 3
Fig. 3. Effect of sub-lethal hyperthermia on changes in expression level of EMT-related markers, analyzed by (a) western blot assay, (b) qRT-PCR, and (c) immunocytochemistry.
Fig. 4
Fig. 4. Effect of sub-lethal hyperthermia on chemo-sensitivity: (a) viability of MCF-7 cells after thermo- and/or chemotherapy; (b) viability of MDA-MB-231 cells after thermo- and/or chemo-therapy.
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