Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Julie K Allen; Guillermo N Armaiz-Pena; Archana S Nagaraja; Nouara C Sadaoui; Tatiana Ortiz; Robert Dood; Merve Ozcan; Danielle M Herder; Monika Haemmerle; Kshipra M Gharpure; Rajesha Rupaimoole; Rebecca A Previs; Sherry Y Wu; Sunila Pradeep; Xiaoyun Xu; Hee Dong Han; Behrouz Zand; Heather J Dalton; Morgan Taylor; Wei Hu; Justin Bottsford-Miller; Myrthala Moreno-Smith; Yu Kang; Lingegowda S Mangala; Cristian Rodriguez-Aguayo; Vasudha Sehgal; Erika L Spaeth; Prahlad T Ram; Stephen T C Wong; Frank C Marini; Gabriel Lopez-Berestein; Steve W Cole; Susan K Lutgendorf; Mariella De Biasi; Anil K Sood

doi:10.1158/0008-5472.CAN-16-1701

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Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Journal article

Open access

Peer reviewed

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Julie K Allen, Guillermo N Armaiz-Pena, Archana S Nagaraja, Nouara C Sadaoui, Tatiana Ortiz, Robert Dood, Merve Ozcan, Danielle M Herder, Monika Haemmerle, Kshipra M Gharpure, …

Cancer research (Chicago, Ill.), Vol.78(12), pp.3233-3242

06/15/2018

DOI: 10.1158/0008-5472.CAN-16-1701

PMCID: PMC6004256

PMID: 29661830

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https://doi.org/10.1158/0008-5472.CAN-16-1701View

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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. .

Membrane Glycoproteins - metabolism

Signal Transduction

Humans

Neoplasms - mortality

Receptors, Adrenergic, beta-3 - metabolism

Tumor Microenvironment - physiology

Peripheral Nerves - pathology

Xenograft Model Antitumor Assays

Feedback, Physiological

Animals

Norepinephrine - metabolism

Guanine Nucleotide Exchange Factors - metabolism

Cell Line, Tumor

Female

Brain-Derived Neurotrophic Factor - metabolism

Mice

Peripheral Nerves - metabolism

Neoplasms - pathology

Cyclic AMP - metabolism

Receptor, trkB - metabolism

Details

Title: Subtitle: Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
Creators: Julie K Allen - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Guillermo N Armaiz-Pena - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Archana S Nagaraja - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Nouara C Sadaoui - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Tatiana Ortiz - Division of Cancer Biology, Ponce Research Institute, Ponce, Puerto Rico
Robert Dood - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Merve Ozcan - Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
Danielle M Herder - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Monika Haemmerle - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Kshipra M Gharpure - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Rajesha Rupaimoole - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Rebecca A Previs - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Sherry Y Wu - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Sunila Pradeep - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Xiaoyun Xu - Systems Medicine and Bioengineering Department, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas
Hee Dong Han - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Behrouz Zand - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Heather J Dalton - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Morgan Taylor - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Wei Hu - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Justin Bottsford-Miller - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Myrthala Moreno-Smith - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Yu Kang - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Lingegowda S Mangala - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Cristian Rodriguez-Aguayo - Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Vasudha Sehgal - Department of System Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Erika L Spaeth - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Prahlad T Ram - Department of System Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Stephen T C Wong - Department of Pathology, Genomic Medicine and Radiology, Houston Methodist Hospital, Weill Cornell Medical College, Houston, Texas
Frank C Marini - Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina
Gabriel Lopez-Berestein - Center for RNA Interference and Non-coding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Steve W Cole - Department of Medicine, Division of Oncology Hematology-Oncology, University of California, Los Angeles, California
Susan K Lutgendorf - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Mariella De Biasi - Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Anil K Sood - Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.78(12), pp.3233-3242
DOI: 10.1158/0008-5472.CAN-16-1701
PMID: 29661830
PMCID: PMC6004256
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: G12 MD007579 / NIMHD NIH HHS T32 CA101642 / NCI NIH HHS P50 CA217685 / NCI NIH HHS R01 CA104825 / NCI NIH HHS U19 CA148127 / NCI NIH HHS U54 CA163071 / NCI NIH HHS P50 CA098258 / NCI NIH HHS R01 CA109298 / NCI NIH HHS U54 CA096300 / NCI NIH HHS R35 CA209904 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA140933 / NCI NIH HHS P20 GM103475 / NIGMS NIH HHS P30 CA016672 / NCI NIH HHS P50 CA083639 / NCI NIH HHS U54 CA096297 / NCI NIH HHS U54 CA163068 / NCI NIH HHS R01 CA193249 / NCI NIH HHS
Language: English
Date published: 06/15/2018
Academic Unit: Psychological and Brain Sciences; Iowa Neuroscience Institute; Obstetrics and Gynecology; Urology
Record Identifier: 9984065885002771

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