Abstract 1062: Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction
Authors: Armaiz-Pena Guillermo N. , Nagaraja Archana S. , Allen Julie K. , Sadaoui Nouara C. , Rupaimoole Rajesha , wu sherry Y. , Pradeep Sunila , Han Hee Dong , Zand Behrouz , Dalton Heather , Previs Rebecca , Taylor Morgan , Bottsford-Miller Justin , Mangala Lingegowda S. , Rodriguez-Aguayo Cristian , Biasi Mariela D. , Lopez-Berestein Gabriel , Cole Steve , Lutgendorf Susan K. , Sood Anil K. 
Published: May 2015

Abstract
Mounting clinical and preclinical evidence supports a key role of sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Sustained adrenergic signaling resulted in increased tumor growth and was correlated with a significant increase in intratumoral nerve density and norepinephrine in several orthotopic models of disease. These effects were completely abrogated by hexamethonium bromide (ganglionic blocker), but not by removal of the adrenal glands. To elucidate mechanism by which tumor cells induce nerve growth, we analyzed gene expression changes and found BDNF to be a key factor upregulated by catecholamine treatment. Treatment with different ADRB agonist and blockers determined that ADRB3 is required for the induction of BDNF. Use of cAMP and Epac agonist/antagonist demonstrated that this axis is required for catecholamine induced BDNF expression. Further analyses revealed that JNK exerts its control of BDNF expression through the regulation of AP-1. In various orthotopic models of disease, chronic stress significantly increased tumor growth and intratumoral innervation, an effect completely blocked by BDNF siRNA-DOPC nanoliposomes. Moreover, BNDF overexpression was sufficient to induce tumor growth and intratumoral innervation. Silencing of TrkB, BDNF receptor, on the host by murine BDNF siRNA-Chitosan nanoparticles blocked the effects of sustained adrenergic signaling on tumor growth and innervation. Additionally, inhibition of host TrkB activity in a transgenic TrkB Kinase-Switch mouse model inoculated with ovarian cancer cells showed that adrenergic induced tumor growth and innervation is mediated by the host TrkB. In cancer patients, high tumor nerve density was significantly associated with increased BDNF and norepinephrine levels, and worse overall survival. Collectively, these data describe a novel pathway for tumor neo-innervation with resultant biological and clinical implications.
Citation Format: Guillermo N. Armaiz-Pena, Archana S. Nagaraja, Julie K. Allen, Nouara C. Sadaoui, Rajesha Rupaimoole, sherry Y. wu, Sunila Pradeep, Hee Dong Han, Behrouz Zand, Heather Dalton, Rebecca Previs, Morgan Taylor, Justin Bottsford-Miller, Lingegowda S. Mangala, Cristian Rodriguez-Aguayo, Mariela De Biasi, Gabriel Lopez-Berestein, Steve Cole, Susan K. Lutgendorf, Anil K. Sood. Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1062. doi:10.1158/1538-7445.AM2014-1062