Understanding the Impact of Adrenergic Stress on the Therapeutic Response of Murine Cancer Models
Eng, Jason Wei-Liang
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Laboratory mice are indispensable tools used in cancer research to model and study multiple aspects of tumor biology. In particular, the development of new therapies for the treatment of cancer has relied heavily on murine tumor models to identify new drug targets, evaluate efficacy, and assess potential toxicities. The information gleaned from these studies has been instrumental in the implementation of clinical trials and the design of novel therapeutic combinations to treat many types of malignancy. However, the responses to new therapies in mouse models does not always accurately reflect the outcomes observed in the clinical setting. A growing awareness of the discrepancies between murine models and patients has led to renewed interest in understanding the basic biology of mice to account for these different responses. Recent studies have indicated that the housing conditions under which all research institutes maintain their laboratory animals may significantly affect their baseline physiology and potentially skew observations made in these experimental models. The research presented in this thesis demonstrates that a critical aspect of the housing conditions, the ambient temperature in which laboratory mice are maintained, can induce a physiological stress that significantly affects the response of tumors to therapy. Throughout this work, we observed that tumors implanted in mice maintained under standard housing temperatures (ST; 22ºC) had significantly poorer responses to apoptosis-inducing therapies compared to mice housed at warmer, thermoneutral temperatures (TT; 30ºC). The improved response in mice housed at TT was associated with lower levels of anti-apoptotic proteins. Additionally, the phosphorylation of the molecule CREB, a transcription factor involved in activating the transcription of many pro-survival proteins, and the molecule BAD, a pro-apoptotic molecule inactivated by phosphorylation at various serine residues, were also decreased in the tumors of mice at TT. Based on previous studies that explore the effects of cool temperatures on mammalian physiology, the maintenance of core body temperature requires the systemic release of the stress hormone, norepinephrine (NE), to induce adaptive thermogenesis in brown adipose and to release metabolites from the liver and white fat to fuel heat production. In addition, recent data demonstrates that stress hormones can significantly enhance the growth and metastasis of tumor cells in both in vitro systems and in animal models. Therefore, we hypothesized that NE, signaling through β-adrenergic receptors, acted as a survival factor that was responsible for the changes in therapeutic response observed in the tumors of mice housed at ST. Using human and murine pancreatic cancer cell lines, we demonstrated that the tumor cells increased their resistance to both Apo2L/TRAIL and cisplatin in response to β-adrenergic receptor activation. Furthermore, pharmacologic blockade of the β-adrenergic receptors, as well as shRNA-mediated silencing specifically of the of β2-adrenergic, led to an improved response to treatment by the tumors of mice at ST; however, as mice at TT were under significantly less stress, we did not observe an increased response to therapies by tumors in mice housed at thermoneutrality when the β-adrenergic receptors were blocked. Taken together, these findings identify for the first time that the nationally mandated housing temperatures in animal research facilities as a major cause of physiological stress in laboratory rodents. Moreover, the impact of this stress on pre-clinical tumor models has the potential to alter the observed responses of cancer cells to various therapies and skew the experimental outcome of certain therapeutic testing.