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.

Long conserved mechanisms maintain homeostasis in living creatures in response to a variety of stresses. However, continuous exposure to stress can result in unabated production of stress hormones, especially catecholamines, which can have detrimental health effects. While the long-term effects of chronic stress have well known physiological consequences, recent discoveries have revealed that stress may affect therapeutic efficacy in cancer. Growing epidemiological evidence reveals strong correlations between long term survival and cancer progression and β-blocker usage in patients. In this review, we summarize the current understanding of how the catecholamines, epinephrine and norepinephrine, affect cancer cell survival and tumor progression. We also highlight new data exploring the potential contributions of stress on immunosuppression in the tumor microenvironment and the implications of these findings for the efficacy of immunotherapies.

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In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating a SC conditional KO of calcineurin B (CnB scko), we assessed the effects of CnB ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnB scko mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnB scko mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3 d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury.

Purpose Researchers studying the response of mice to stress generally use mice housed under standard, nationally-enforced conditions as controls. Few investigators are concerned whether basic, physical aspects of mouse housing could also be a source of stress, capable of influencing the subsequent impact of an experimentally applied stressor. We have recently become aware of the potential for standard housing conditions to influence important physiological and immunological properties in mice. Materials and Methods Here, we sought to determine whether housing mice at standard temperature (ST; 22°C) versus thermoneutral temperature (TT; 30°C) influences baseline expression of heat shock proteins (HSPs) and their typical induction following a whole body heating. Results There were not significant differences in baseline expression of HSPs at ST and TT. However, in several cases, we induction of HSP70, HSP110, and HSP90 in tissues of mice maintained at ST was greater than at ST, following 6 hours of heating which elevated core body temperature to 39.5°C. This loss of HSP induction was also obtained when mice housed at ST were given propranolol, a β-adrenergic receptor antagonist, used clinically to treat hypertension and stress. Conclusions Taken together, these data show that housing temperature has a significant influence on the expression of HSPs in mice after whole body heating and should be considered when stress responses are studied in mice.