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Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

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.

SUBMITTER: Allen JK

PROVIDER: S-EPMC6004256 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

Allen Julie K JK Armaiz-Pena Guillermo N GN Nagaraja Archana S AS Sadaoui Nouara C NC Ortiz Tatiana T Dood Robert R Ozcan Merve M Herder Danielle M DM Haemmerle Monika M Gharpure Kshipra M KM Rupaimoole Rajesha R Previs Rebecca A RA Wu Sherry Y SY Pradeep Sunila S Xu Xiaoyun X Han Hee Dong HD Zand Behrouz B Dalton Heather J HJ Taylor Morgan M Hu Wei W Bottsford-Miller Justin J Moreno-Smith Myrthala M Kang Yu Y Mangala Lingegowda S LS Rodriguez-Aguayo Cristian C Sehgal Vasudha V Spaeth Erika L EL Ram Prahlad T PT Wong Stephen T C STC Marini Frank C FC Lopez-Berestein Gabriel G Cole Steve W SW Lutgendorf Susan K SK De Biasi Mariella M Sood Anil K AK

Cancer research 20180416 12

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 ...[more]

PMID: 29661830

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Project description:Patients with diabetes mellitus can develop cardiac dysfunction in the absence of underlying coronary artery disease or hypertension; a condition defined as diabetic cardiomyopathy. Mice lacking the intracellular protein kinase Akt2 develop a syndrome that is similar to diabetes mellitus type 2. Expression profiling of akt2(-/-) myocardium revealed that Rab4a, a GTPase involved in glucose transporter 4 translocation and ?-adrenergic receptor (?AR) recycling to the plasma membrane, was significantly induced. We therefore hypothesized that Akt2 deficiency increases myocardial ?-adrenergic sensitivity. Confirmatory analysis revealed up-regulation of Rab4a mRNA and protein in akt2(-/-) myocardium. In cultured cardiomyocyte experiments, Rab4a was induced by pharmacological inhibition of Akt as well as by specific knockdown of Akt2 with siRNA. Isolated akt2(-/-) hearts were hypersensitive to isoproterenol (ISO) but exhibited normal sensitivity to forskolin. Prolonged ISO treatment led to increased cardiac hypertrophy in akt2(-/-) mice compared to wild type mice. In addition, spontaneous hypertrophy was noted in aged akt2(-/-) hearts that was inhibited by treatment with the ?AR blocker propranolol. In agreement with previous results demonstrating increased fatty acid oxidation rates in akt2(-/-) myocardium, we found increased peroxisome proliferator-activated receptor ? (PPAR?) activity in the hearts of these animals. Interestingly, increased myocardial Rab4a expression was present in mice with cardiac-specific overexpression of PPAR? and was also observed upon stimulation of PPAR? activity in cultured cardiomyocytes. Accordingly, propranolol attenuated the development of cardiac hypertrophy in the PPAR? transgenic mice as well. Our results indicate that reduced Akt2 leads to up-regulation of Rab4a expression in cardiomyocytes in a cell-autonomous fashion that may involve activation of PPAR?. This maladaptive response is associated with hypersensitivity of akt2(-/-) myocardium to ?-adrenergic stimulation.

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Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

Publications

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.

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