Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Allen J. K. , Armaiz-Pena G. N. , Nagaraja A. S. , Sadaoui N. C. , Ortiz T., Dood R., ...More

CANCER RESEARCH, vol.78, no.12, pp.3233-3242, 2018 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 78 Issue: 12
  • Publication Date: 2018
  • Doi Number: 10.1158/0008-5472.can-16-1701
  • Journal Name: CANCER RESEARCH
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.3233-3242


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.