Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
CANCER RESEARCH, vol.78, no.12, pp.3233-3242, 2018 (SCI-Expanded, Scopus)
- 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 (SCI-EXPANDED), Scopus
- Page Numbers: pp.3233-3242
- Open Archive Collection: AVESIS Open Access Collection
- Hacettepe University Affiliated: Yes
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.