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 - Funding Information:
G.N. Armaiz-Pena was partially supported by an institutional development award from the NIGMS P20GM103475, a grant from the Puerto Rico Science, Technology and Research Trust, and the following grants NCI U54CA163071, U54CA163068, and G12MD007579. A.S. Nagaraja was supported, in part, by the CPRIT Graduate Scholar Fellowship (RP140106). B. Zand, H.J. Dalton, R.A. Previs, and J. Bottsford-Miller were supported by an NIH T32 Training Grant CA101642. S.K. Lutgendorf was supported by NIH grants CA140933 and CA193249. S.Y. Wu was supported by Ovarian Cancer Research Fund, Inc. and
Funding Information:
Cancer Prevention Research Institute of Texas training grants (RP101502 and RP101489). M. De Biasi was supported by NIH grant U19CA148127, Area 2. This work was also supported in part by NIH grants (CA109298, P50 CA217685, R35 CA209904, P50CA098258, CA016672, U54CA96300, and U54CA96297), Ovarian Cancer Research Fund Program Project Development Grant, the Frank McGraw Memorial Chair in Cancer Research, the American Cancer Society Research Professor Award, and the Blanton-Davis Ovarian Cancer Research Program to A.K. Sood.
Publisher Copyright:
© 2018 AACR.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85048711132&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-16-1701c
DO - 10.1158/0008-5472.CAN-16-1701c
M3 - Article
C2 - 29661830
AN - SCOPUS:85048711132
VL - 78
SP - 3233
EP - 3242
JO - Cancer research
JF - Cancer research
SN - 0008-5472
IS - 12
ER -