TY - JOUR
T1 - Sustained adrenergic signaling promotes intratumoral innervation through BDNF induction
AU - Allen, Julie K.
AU - Armaiz-Pena, Guillermo N.
AU - Nagaraja, Archana S.
AU - Sadaoui, Nouara C.
AU - Ortiz, Tatiana
AU - Dood, Robert
AU - Ozcan, Merve
AU - Herder, Danielle M.
AU - Haemmerle, Monika
AU - Gharpure, Kshipra M.
AU - Rupaimoole, Rajesha
AU - Previs, Rebecca A.
AU - Wu, Sherry Y.
AU - Pradeep, Sunila
AU - Xu, Xiaoyun
AU - Han, Hee Dong
AU - Zand, Behrouz
AU - Dalton, Heather J.
AU - Taylor, Morgan
AU - Hu, Wei
AU - Bottsford-Miller, Justin
AU - Moreno-Smith, Myrthala
AU - Kang, Yu
AU - Mangala, Lingegowda S.
AU - Rodriguez-Aguayo, Cristian
AU - Sehgal, Vasudha
AU - Spaeth, Erika L.
AU - Ram, Prahlad T.
AU - Wong, Stephen T.C.
AU - Marini, Frank C.
AU - Lopez-Berestein, Gabriel
AU - Cole, Steve W.
AU - Lutgendorf, Susan K.
AU - De Biasi, Mariella
AU - Sood, Anil K.
N1 - Publisher Copyright:
© 2018 AACR.
PY - 2018/6/15
Y1 - 2018/6/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1701c
DO - 10.1158/0008-5472.CAN-16-1701c
M3 - Article
C2 - 29661830
AN - SCOPUS:85048711132
SN - 0008-5472
VL - 78
SP - 3233
EP - 3242
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -