Housing temperature-induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation

Nat Commun. 2015 Mar 10;6:6426. doi: 10.1038/ncomms7426.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Albumins / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Isoproterenol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • Paclitaxel / pharmacology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Adrenergic, beta-2 / genetics*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Signal Transduction
  • Stress, Physiological
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Temperature
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • 130-nm albumin-bound paclitaxel
  • Adrenergic beta-Agonists
  • Albumins
  • Antineoplastic Agents
  • Bcl2l1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Adrenergic, beta-2
  • TNF-Related Apoptosis-Inducing Ligand
  • bcl-X Protein
  • Bcl2 protein, mouse
  • Isoproterenol
  • Paclitaxel
  • Cisplatin