The Impact of Housing Temperature-Induced Chronic Stress on Preclinical Mouse Tumor Models and Therapeutic Responses: An Important Role for the Nervous System.
In the last 10-15 years, there has been a recognition that the catecholamines (norepinephrine, NE, and epinephrine, Epi) released by the sympathetic nervous system under stressful conditions promote tumor growth through a variety of mechanisms. Tumors recruit autonomic nerves during their development and NE is then released locally in the tumor microenvironment (TME). Acting through adrenergic receptors present on a variety of cells in the TME, NE and Epi induce proliferation, resistance to apoptosis, epithelial to mesenchymal transition, metastasis of tumor cells, angiogenesis, and inflammation in the TME. These pre-clinical studies have been conducted in mouse models whose care and housing parameters are outlined in "The Guide for the Care and Use of Laboratory Animals [1]. In particular, the Guide mandates that mice be housed at standardized sub-thermoneutral temperatures; however, this causes a state of chronic cold-stress and elevated levels of NE. Although mice are able to maintain a normal body temperature when kept at these cool temperatures, it is becoming clear that this cold-stress is sufficient to activate physiological changes which affect experimental outcomes. We find that when mice are housed under standard, sub-thermoneutral temperatures (~22 °C, ST), tumor growth is significantly greater than when mice are housed at thermoneutrality (~30 °C TT). We also find that the anti-tumor immune response is suppressed at ST and this immunosuppression can be reversed by housing mice at TT or by administration of propranolol (a β-adrenergic receptor antagonist) to mice housed at ST. Furthermore, at ST tumors are more resistant to therapy and can also be sensitized to cytotoxic therapies by housing mice at TT or by treating mice with propranolol. The implications of these observations are particularly relevant to the way in which experiments conducted in preclinical models are interpreted and the findings implemented in the clinic. It may be that the disappointing failure of many new therapies to fulfill their promise in the clinic is related to an incomplete preclinical assessment in mouse models. Further, an expanded understanding of the efficacy of a therapy alone or in combination obtained by testing under a wider range of conditions would better predict how patients, who are under various levels of stress, might respond in a clinical setting. This may be particularly important to consider since we now appreciate that long term outcome of many therapies depends on eliciting an immune response.It is clear that the outcome of metabolic experiments, immunological investigations and therapeutic efficacy testing in tumors of mice housed at ST is restricted and expanding these experiments to include results obtained at TT may provide us with valuable information that would otherwise be overlooked.