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Cancer Res. 2018 Jun 15;78(12):3233-3242. doi: 10.1158/0008-5472.CAN-16-1701. Epub 2018 Apr 16.

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
2
Division of Cancer Biology, Ponce Research Institute, Ponce, Puerto Rico.
3
Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
4
Systems Medicine and Bioengineering Department, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas.
5
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
6
Department of System Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
7
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
8
Department of Pathology, Genomic Medicine and Radiology, Houston Methodist Hospital, Weill Cornell Medical College, Houston, Texas.
9
Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina.
10
Center for RNA Interference and Non-coding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
11
Department of Medicine, Division of Oncology Hematology-Oncology, University of California, Los Angeles, California.
12
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa.
13
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa.
14
Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa.
15
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
16
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. asood@mdanderson.org.
17
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
#
Contributed equally

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.Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR.

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