Abstract PS19-04: Standard temperature husbandry increases tumor aggressiveness via chronic cold stress in murine mammary cancer models

Abstract

Correct interpretation of disease progression and therapeutic responses in mouse models of breast cancer requires interrogation of models and conditions that faithfully recapitulate human disease and conditions that mimic clinical intervention. Historically, standard temperature (ST) for in vivo murine research has been approximately 70-72°F (21-22°C), mimicking ambient temperatures in laboratories that are comfortable for researchers. However, previous work from the Repasky lab demonstrated that ST housing results in chronic cold stress and immune suppression mediated by an increase in norepinrephrine (NE) levels, leading to increased tumor aggressiveness. In contrast, syngeneic murine mammary tumors in mice housed at higher temperatures [~ 82°F] grew more slowly and resulted in fewer metastases. Based on these findings, we investigated tumor progression and metastasis in a temperature dose response in two syngeneic murine mammary tumor models: the balb/c-4T1 model and the c57bl6/E0771-LMB (a lung metastatic variant of E0771 cells) model.Mice were acclimatized in rooms with three different ambient temperaures and challenged with tumor cells. ST was maintained at 70-72°F, while mid-temperature (MT) was maintained at 78-80°F, and high temperature (HT) was maintained at 84-85°F. Compared to ST and MT, an ambient temperature of 84-85°F resulted in a statistically significant delay in tumor formation and decreased primary tumor growth by unpaired t-test (p=.0006) At day 13, when 4T1 tumors are typically well-initiated and measurable by caliper, mean tumor volumes in the ST-housed mice were significantly larger than the HT group. At day 21, ST tumors means were 4 times larger than HT. In the E0771-LMB model, mean tumor volumes on day 14 were nearly 3 times larger in ST-housed mice than HT. At day 27, the mean tumor volumes were 2 times larger in the ST group compared to HT-housed mice. Data on metastasis will be presented at the meeting. Mean NE levels in mice housed at ST were twice as high as those at HT, providing ancillary evidence that traditional “standard” temperatures are a significant stressor for mice (p=.0091).These data demonstrate the potential for misleading interpretations of biological significance of chronic cold stress when modeling immunocompetent tumor progression [conditions almost universally employed in most studies]. Furthermore, these data demonstrate that the presence of chronic cold stress and its immunosuppressive effects call into question the interpretation of many previous studies completed at or near standard temperature and may suggest the need to increase ambient temperatures in syngeneic experiments in order to more accurately model human disease. Citation Format: Darius O Gaymon, Marc Lippman, Patricia Foley, Philip Miller. Standard temperature husbandry increases tumor aggressiveness via chronic cold stress in murine mammary cancer models [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-04.