51. Sustained Adrenergic Signaling Promotes Intratumoral Innervation Through Bdnf Induction
- Author
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Archana S. Nagaraja, Monika Haemmerle, Morgan Taylor, Danielle M. Herder, Stephen T. C. Wong, Merve Ozcan, Nouara C. Sadaoui, Mariella De Biasi, Frank C. Marini, Prahlad T. Ram, Lingegowda S. Mangala, Heather J. Dalton, Steve W. Cole, Wei Hu, Kshipra M. Gharpure, Susan K. Lutgendorf, Hee Dong Han, Anil K. Sood, Vasudha Sehgal, Sherry Y. Wu, Sunila Pradeep, Rebecca A. Previs, Yu Kang, Rajesha Rupaimoole, Erika L. Spaeth, Xiaoyun Xu, Myrthala Moreno-Smith, R.L. Dood, Behrouz Zand, Cristian Rodriguez-Aguayo, Tatiana Ortiz, Julie K. Allen, Guillermo N. Armaiz-Pena, Gabriel Lopez-Berestein, Justin Bottsford-Miller, and Temel Onkoloji
- Subjects
0301 basic medicine ,Cancer Research ,Adrenergic ,Receptor tyrosine kinase ,Mice ,Norepinephrine ,03 medical and health sciences ,Neurotrophic factors ,Cell Line, Tumor ,Neoplasms ,Cyclic AMP ,Tumor Microenvironment ,Animals ,Guanine Nucleotide Exchange Factors ,Humans ,Receptor, trkB ,Medicine ,Peripheral Nerves ,Receptor ,Intratumoral innervation ,Feedback, Physiological ,Brain-derived neurotrophic factor ,Tumor microenvironment ,Membrane Glycoproteins ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,Bdnf induction ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Oncology ,Adrenergic signaling ,Receptors, Adrenergic, beta-3 ,biology.protein ,Cancer research ,Female ,Biyokimya. Hücre biyolojisi. Hücre genetiği ,Signal transduction ,business ,Signal Transduction ,Neurotrophin - Abstract
Mounting clinical and preclinical evidence supports a key role for 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. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233–42. ©2018 AACR.
- Published
- 2018