Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation

Jason W.L. Eng; Chelsey B. Reed; Kathleen M. Kokolus; Rosemarie Pitoniak; Adam Utley; Mark J. Bucsek; Wen Wee Ma; Elizabeth A. Repasky; Bonnie L. Hylander

doi:10.1038/ncomms7426

Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β₂-adrenergic receptor activation

Jason W.L. Eng, Chelsey B. Reed, Kathleen M. Kokolus, Rosemarie Pitoniak, Adam Utley, Mark J. Bucsek, Wen Wee Ma, Elizabeth A. Repasky, Bonnie L. Hylander

Medical Oncology

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74 Scopus citations

Abstract

Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30^°C compared with the standard temperature of 22^°C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22^°C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a β 2-adrenergic receptor antagonist to mice housed at 22^°C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.

Original language	English (US)
Article number	6426
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7426
State	Published - Mar 10 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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@article{0a82a46d49a24649905b580655df6477,

title = "Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation",

abstract = "Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30°C compared with the standard temperature of 22°C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22°C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a β 2-adrenergic receptor antagonist to mice housed at 22°C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.",

author = "Eng, {Jason W.L.} and Reed, {Chelsey B.} and Kokolus, {Kathleen M.} and Rosemarie Pitoniak and Adam Utley and Bucsek, {Mark J.} and Ma, {Wen Wee} and Repasky, {Elizabeth A.} and Hylander, {Bonnie L.}",

note = "Funding Information: We thank Jeanne Prendergast for editorial assistance and Drs Scott Abrams, Sandra Gollnick and David Farrar for their valuable experimental suggestions. We also thank Genentech for the generous donation of Apo2L/TRAIL used in this work. This work was supported by National Institute of Health Grants R01 CA135368, R01 CA108888 and T32 CA085183. Work in this manuscript used shared resources supported by the Roswell Park Cancer Institute{\textquoteright}s Comprehensive Cancer Center Support Grant CA016056. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

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day = "10",

doi = "10.1038/ncomms7426",

language = "English (US)",

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AU - Eng, Jason W.L.

AU - Reed, Chelsey B.

AU - Kokolus, Kathleen M.

AU - Pitoniak, Rosemarie

AU - Utley, Adam

AU - Bucsek, Mark J.

AU - Ma, Wen Wee

AU - Repasky, Elizabeth A.

AU - Hylander, Bonnie L.

N1 - Funding Information: We thank Jeanne Prendergast for editorial assistance and Drs Scott Abrams, Sandra Gollnick and David Farrar for their valuable experimental suggestions. We also thank Genentech for the generous donation of Apo2L/TRAIL used in this work. This work was supported by National Institute of Health Grants R01 CA135368, R01 CA108888 and T32 CA085183. Work in this manuscript used shared resources supported by the Roswell Park Cancer Institute’s Comprehensive Cancer Center Support Grant CA016056. Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/3/10

Y1 - 2015/3/10

N2 - Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30°C compared with the standard temperature of 22°C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22°C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a β 2-adrenergic receptor antagonist to mice housed at 22°C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.

AB - Cancer research relies heavily on murine models for evaluating the anti-tumour efficacy of therapies. Here we show that the sensitivity of several pancreatic tumour models to cytotoxic therapies is significantly increased when mice are housed at a thermoneutral ambient temperature of 30°C compared with the standard temperature of 22°C. Further, we find that baseline levels of norepinephrine as well as the levels of several anti-apoptotic molecules are elevated in tumours from mice housed at 22°C. The sensitivity of tumours to cytotoxic therapies is also enhanced by administering a β 2-adrenergic receptor antagonist to mice housed at 22°C. These data demonstrate that standard housing causes a degree of cold stress sufficient to impact the signalling pathways related to tumour-cell survival and affect the outcome of pre-clinical experiments. Furthermore, these data highlight the significant role of host physiological factors in regulating the sensitivity of tumours to therapy.

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Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β₂-adrenergic receptor activation

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