PMID- 29661830 OWN - NLM STAT- MEDLINE DCOM- 20190730 LR - 20231004 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 78 IP - 12 DP - 2018 Jun 15 TI - Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. PG - 3233-3242 LID - 10.1158/0008-5472.CAN-16-1701 [doi] 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. Cancer Res; 78(12); 3233-42. (c)2018 AACR. CI - (c)2018 American Association for Cancer Research. FAU - Allen, Julie K AU - Allen JK AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Armaiz-Pena, Guillermo N AU - Armaiz-Pena GN AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Nagaraja, Archana S AU - Nagaraja AS AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Sadaoui, Nouara C AU - Sadaoui NC AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Ortiz, Tatiana AU - Ortiz T AD - Division of Cancer Biology, Ponce Research Institute, Ponce, Puerto Rico. FAU - Dood, Robert AU - Dood R AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Ozcan, Merve AU - Ozcan M AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. AD - Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey. FAU - Herder, Danielle M AU - Herder DM AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Haemmerle, Monika AU - Haemmerle M AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Gharpure, Kshipra M AU - Gharpure KM AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Rupaimoole, Rajesha AU - Rupaimoole R AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Previs, Rebecca A AU - Previs RA AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Wu, Sherry Y AU - Wu SY AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Pradeep, Sunila AU - Pradeep S AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Xu, Xiaoyun AU - Xu X AD - Systems Medicine and Bioengineering Department, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas. FAU - Han, Hee Dong AU - Han HD AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Zand, Behrouz AU - Zand B AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Dalton, Heather J AU - Dalton HJ AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Taylor, Morgan AU - Taylor M AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Hu, Wei AU - Hu W AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Bottsford-Miller, Justin AU - Bottsford-Miller J AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Moreno-Smith, Myrthala AU - Moreno-Smith M AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Kang, Yu AU - Kang Y AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Mangala, Lingegowda S AU - Mangala LS AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Rodriguez-Aguayo, Cristian AU - Rodriguez-Aguayo C AUID- ORCID: 0000-0002-7880-7723 AD - Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Sehgal, Vasudha AU - Sehgal V AD - Department of System Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Spaeth, Erika L AU - Spaeth EL AD - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Ram, Prahlad T AU - Ram PT AD - Department of System Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Wong, Stephen T C AU - Wong STC AD - Systems Medicine and Bioengineering Department, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, Texas. AD - Department of Pathology, Genomic Medicine and Radiology, Houston Methodist Hospital, Weill Cornell Medical College, Houston, Texas. FAU - Marini, Frank C AU - Marini FC AD - Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina. FAU - Lopez-Berestein, Gabriel AU - Lopez-Berestein G AD - Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. AD - Center for RNA Interference and Non-coding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. FAU - Cole, Steve W AU - Cole SW AD - Department of Medicine, Division of Oncology Hematology-Oncology, University of California, Los Angeles, California. FAU - Lutgendorf, Susan K AU - Lutgendorf SK AD - Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa. AD - Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa. AD - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. FAU - De Biasi, Mariella AU - De Biasi M AD - Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Sood, Anil K AU - Sood AK AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. asood@mdanderson.org. AD - Center for RNA Interference and Non-coding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. AD - Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - U01 CA213759/CA/NCI NIH HHS/United States GR - P20 GM103475/GM/NIGMS NIH HHS/United States GR - P50 CA217685/CA/NCI NIH HHS/United States GR - U54 CA096297/CA/NCI NIH HHS/United States GR - R35 CA209904/CA/NCI NIH HHS/United States GR - U54 CA163068/CA/NCI NIH HHS/United States GR - P50 CA098258/CA/NCI NIH HHS/United States GR - U54 CA151668/CA/NCI NIH HHS/United States GR - R01 CA193249/CA/NCI NIH HHS/United States GR - U54 CA096300/CA/NCI NIH HHS/United States GR - P50 CA083639/CA/NCI NIH HHS/United States GR - R01 CA092309/CA/NCI NIH HHS/United States GR - T32 CA101642/CA/NCI NIH HHS/United States GR - U19 CA148127/CA/NCI NIH HHS/United States GR - P30 CA086862/CA/NCI NIH HHS/United States GR - R01 CA109298/CA/NCI NIH HHS/United States GR - G12 MD007579/MD/NIMHD NIH HHS/United States GR - R01 CA104825/CA/NCI NIH HHS/United States GR - R01 CA140933/CA/NCI NIH HHS/United States GR - U54 CA163071/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PT - Video-Audio Media DEP - 20180416 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (ADRB3 protein, human) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Guanine Nucleotide Exchange Factors) RN - 0 (Membrane Glycoproteins) RN - 0 (RAPGEF3 protein, human) RN - 0 (Receptors, Adrenergic, beta-3) RN - 7171WSG8A2 (BDNF protein, human) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) RN - X4W3ENH1CV (Norepinephrine) CIN - Cancer Res. 2018 Oct 15;78(20):6022. PMID: 30275020 MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Line, Tumor MH - Cyclic AMP/metabolism MH - *Feedback, Physiological MH - Female MH - Guanine Nucleotide Exchange Factors/metabolism MH - Humans MH - Membrane Glycoproteins/metabolism MH - Mice MH - Neoplasms/mortality/*pathology MH - Norepinephrine/*metabolism MH - Peripheral Nerves/metabolism/pathology MH - Receptor, trkB/metabolism MH - Receptors, Adrenergic, beta-3/*metabolism MH - Signal Transduction MH - Tumor Microenvironment/physiology MH - Xenograft Model Antitumor Assays PMC - PMC6004256 MID - NIHMS960976 COIS- The authors declare no competing financial interests. EDAT- 2018/04/18 06:00 MHDA- 2019/07/31 06:00 PMCR- 2019/06/15 CRDT- 2018/04/18 06:00 PHST- 2016/06/28 00:00 [received] PHST- 2017/04/04 00:00 [revised] PHST- 2018/04/10 00:00 [accepted] PHST- 2018/04/18 06:00 [pubmed] PHST- 2019/07/31 06:00 [medline] PHST- 2018/04/18 06:00 [entrez] PHST- 2019/06/15 00:00 [pmc-release] AID - 0008-5472.CAN-16-1701 [pii] AID - 10.1158/0008-5472.CAN-16-1701 [doi] PST - ppublish SO - Cancer Res. 2018 Jun 15;78(12):3233-3242. doi: 10.1158/0008-5472.CAN-16-1701. Epub 2018 Apr 16.