Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

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. Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. .

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

“…We have shown that the ameloblastoma epithelium expresses detectable levels of the neurotrophins NGF and BDNF, as well as the neurotrophin receptors TRKA, TRKB, and P75/NGFR. Both NGF and BDNF have already been shown to promote tumor innervation in other tissues [29,72,74,79]. In addition to promoting cancer innervation, neurotrophin-mediated signaling has been shown to directly drive tumor onset and progression [72,74,[80][81][82].…”

Tumor Neurobiology and the War of Nerves in Cancer

“…In pancreatic (10) and gastric (28) cancers, where NGF production by cancer cells drives axonogenesis, the value of NGF as a prognostic biomarker should be investigated. In breast cancer, the expression of NGF is associated with lymph node invasion (30), and in ovarian cancer the production of BDNF drives adrenergic nerve infiltration (71). Therefore, given their role in tumor innervation, neurotrophic factors may be used as diagnostic and prognostic cancer biomarkers.…”

Stress, inflammation, and eicosanoids: an emerging perspective

“…In addition to enhanced tumor angiogenesis, tumor innervation might further enhance tumorigenesis by enriching the tumor microenvironment with catecholamines released by the newly formed nerve endings. We and others have found that in response to catecholamines, tumor cells release neurotrophins (BDNF/NGF), which leads to increased tumor innervation and growth in restraint stress tumor models [59, 60]. There is evidence to show that behavioral stress contributes to an increase in catecholaminergic nerve fibers within lymphoid organs in primates, an indication of a long-term regulatory influence of stress on immune responses [61].…”