Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Julie K. Allen(The University of Texas MD Anderson Cancer Center), Guillermo N. Armaiz-Peña(The University of Texas MD Anderson Cancer Center), Archana S. Nagaraja(The University of Texas MD Anderson Cancer Center), Nouara C. Sadaoui(The University of Texas MD Anderson Cancer Center), Tatiana Ortíz(Ponce Health Sciences University), Robert Dood(The University of Texas MD Anderson Cancer Center), Merve Ozcan(The University of Texas MD Anderson Cancer Center), Danielle M. Herder(The University of Texas MD Anderson Cancer Center), Monika Haemmerle(The University of Texas MD Anderson Cancer Center), Kshipra M. Gharpure(The University of Texas MD Anderson Cancer Center), Rajesha Rupaimoole(The University of Texas MD Anderson Cancer Center), Rebecca A. Previs(The University of Texas MD Anderson Cancer Center), Sherry Y. Wu(The University of Texas MD Anderson Cancer Center), Sunila Pradeep(The University of Texas MD Anderson Cancer Center), Xiaoyun Xu(Cornell University), Hee Dong Han(The University of Texas MD Anderson Cancer Center), Behrouz Zand(The University of Texas MD Anderson Cancer Center), Heather J. Dalton(The University of Texas MD Anderson Cancer Center), Morgan Taylor(The University of Texas MD Anderson Cancer Center), Wei Hu(The University of Texas MD Anderson Cancer Center), Justin Bottsford-Miller(The University of Texas MD Anderson Cancer Center), Myrthala Moreno‐Smith(The University of Texas MD Anderson Cancer Center), Yu Kang(The University of Texas MD Anderson Cancer Center), Lingegowda S. Mangala(The University of Texas MD Anderson Cancer Center), Cristian Rodriguez‐Aguayo(The University of Texas MD Anderson Cancer Center), Vasudha Sehgal(The University of Texas MD Anderson Cancer Center), Erika L. Spaeth(The University of Texas MD Anderson Cancer Center), Prahlad T. Ram(The University of Texas MD Anderson Cancer Center), Stephen T.C. Wong(Cornell University), Frank C. Marini(Wake Forest University), Gabriel Lopez‐Berestein(The University of Texas MD Anderson Cancer Center), Steve W. Cole(University of California, Los Angeles), Susan K. Lutgendorf(University of Iowa), Mariella De Biasi(University of Pennsylvania), Anil K. Sood(The University of Texas MD Anderson Cancer Center)
Cancer Research
April 16, 2018
10.1158/0008-5472.can-16-1701
Cited by 130Open Access
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Abstract

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.

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