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-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.

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…We also found that NE levels were higher in tumors of mice at ST compared to TT [44]. In more recent work, M. Bucsek et al (manuscript in preparation) find that, at ST, tumor growth can be significantly delayed by administration of propranolol (a b-adrenergic receptor antagonist), and 30-32 8C.…”

“…At thermoneutrality the mechanisms underlying successful antitumor immune responses may differ from those mechanisms at ST. For example, recent evidence shows that exposure of mice to mild cold stress (ST) affects the differentiation pathway of macrophages such that IL-4-mediated 'alternative activation' of adipose tissue macrophages (which secrete NE) occurs to promote thermogenesis in BAT and lipolysis in WAT [43]. These alternatively activated macrophages could themselves be another source of immunosuppression.We also found that NE levels were higher in tumors of mice at ST compared to TT [44]. In more recent work, M. Bucsek et al (manuscript in preparation) find that, at ST, tumor growth can be significantly delayed by administration of propranolol (a b-adrenergic receptor antagonist), and 30-32 8C.…”

“…These results suggest that elevated NE levels at ST interfere with obtaining a full understanding of the GVHD phenotype in this mouse model, and again demonstrate that immunological responses are generally impaired in mice housed at ST. Further research will be necessary to determine how reducing GVHD through stress signaling could impact possible tumor recurrence in this model. With regard to mild cold stress (and resultant adrenergic signaling in tumor cells), Eng et al [44] found that the level of NE in pancreatic tumors of mice at ST was significantly higher than in tumors of mice at TT. This increased adrenergic signaling induced increased expression of anti-apoptotic molecules, including Bcl-Xl, Bxl-2, and Mcl-1, as well as phosphorylated BAD, at ST compared to TT.…”

“…The key to reproducibility is accurate reporting of these seemingly mundane details, which potentially have large effects ' [87]. Although housing temperature was not included as a factor in these analyses, studies are accumulating in which experimental outcomes differ depending on the ambient temperature; these are summarized in Figure 1 [7,10,11,19,27,28,40,42,44,46,48,63,66,67,70,79,84,[88][89][90][91][92][93][94] biomedical applications, and how this condition may influence decisions for translation to the clinic (see Outstanding Questions). It is likely that many, if not all, of the metabolic abnormalities noted previously in mouse models stem largely from chronic mild cold stress and the increase in adaptive thermogenesis.…”

“…Comparisons of BAT by MRI could also prove to be a valuable and relevant biomarker of the degree of cold-stress in experimental mice at different ambient temperatures [40]. Sleep [79,94 ] Obesity [63,66,67 [7,10,12,[27][28][29]37,40,[42][43][44]46,47,63,66,67,70,71,79,84,89,93,94]). Several other conditions or phenomena that are modeled in mice and are likely to be influenced by housing temperature, but for which there is little or no published information are also listed (followed by ?).…”