Abstract 1605: Social stress stimulates the progression of pancreatic cancer xenografts in nude mice
Authors: Hussein A. Al-Wadei, Mohammed F. Ullah, Joel R. Brody, Hildegard M. Schuller
Journal: Cancer Research (2011)

Abstract Pancreatic ductal adenocarcinoma (PDAC) cancer is a highly aggressive cancer with poor prognosis due to limited chemosensitivity to currently available therapeutic regimens. Smoking, diabetes and pancreatitis are risk factors for PDAC. Our laboratory has shown that agonist for β-ARs promoted the progression of pancreatic cancer in hamsters while the beta-blocker propranolol had strong cancer preventive effects. The stress neurotransmitters noradrenaline and adrenaline are the physiological agonists for β-ARs. They are released from nerve endings and the adrenal medulla in response to nicotinic acetylcholine receptor (nAChR) stimulation by acetylcholine. The neurotransmitter γ-aminobutyric acid (GABA) acts as the physiological inhibitor of β-adrenergic signaling by blocking Gα1-mediated activation of adenylyl cyclase. The present study has tested the hypothesis that social stress stimulates the growth of human PDAC xenografts via nAChR-mediated release of stress neurotransmitters and the associated activation of β-adrenergic signaling. Groups of nude mice were exposed to social stress 4 weeks prior to subcutaneous injection with PDAC cell lines Panc-1 (with activating point mutation in K-ras) and BxPc-3 (without K-ras mutation) and stress continued for another 4 weeks. Mice not exposed to stress served as controls. The developing xenografts were measured weekly. At the end of the experiment, the systemic levels of noradrenaline, adrenaline, cortisol GABA in serum and xenograft tissues and cAMP in the cellular fraction of blood and in xenograft tissues were assessed by immunoassays. In addition, the protein expression of nAChR subunits α7, α4, α3, α5, the expression of β-adrenergic signaling proteins p-CREB and p-ERK and of the GABA synthesizing enzymes GAD67 and GAD65 were assessed by Western blotting in xenograft tissues. Our results show a significant stimulation of xenograft growth by social stress accompanied by elevated levels of stress neurotransmitters, cortisol and cAMP. An enhanced expression of nAChR subunits α3, α4, α5 and α7 as well as of β-adrenergic pathway proteins were found in xenografts of stressed animals. By contrast the inhibitory neurotransmitter GABA and both GAD enzymes were downregulated in animals exposed to stress. These findings suggest that social stress stimulates the progression of PDAC via nAChR-dependent upregulation of cancer stimulating noradrenaline/adrenaline and their associated β-adrenergic signaling while simultaneously reducing inhibitory GABA thereby counteracting the efficacy of cancer therapeutics. Psychological stress reduction strategies as well as pharmacological inhibition of this PDAC stimulating pathway by beta-blockers or GABA-ergic agents should be considered to improve the responsiveness to cancer therapeutics in PDAC patients. Supported by Challenge grant 1RC1CA144640 with the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1605. doi:10.1158/1538-7445.AM2011-1605