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Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

2018; American Association for Cancer Research; Volume: 78; Issue: 12 Linguagem: Inglês

10.1158/0008-5472.can-16-1701

1538-7445

Julie K. Allen, Guillermo N. Armaiz-Peña, Archana S. Nagaraja, Nouara C. Sadaoui, Tatiana Ortíz, Robert Dood, Merve Ozcan, Danielle M. Herder, Monika Haemmerle, Kshipra M. Gharpure, Rajesha Rupaimoole, Rebecca A. Previs, Sherry Y. Wu, Sunila Pradeep, Xiaoyun Xu, Hee Dong Han, Behrouz Zand, Heather J. Dalton, Morgan Taylor, Wei Hu, Justin Bottsford-Miller, Myrthala Moreno‐Smith, Yu Kang, Lingegowda S. Mangala, Cristian Rodriguez‐Aguayo, Vasudha Sehgal, Erika L. Spaeth, Prahlad T. Ram, Stephen T.C. Wong, Frank C. Marini, Gabriel López-Berestein, Steve W. Cole, Susan K. Lutgendorf, Mariella De Biasi, Anil K. Sood,

Pediatric Pain Management Techniques

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.