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. 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

Julie K Allen #  1 , Guillermo N Armaiz-Pena #  1 , Archana S Nagaraja #  1 , Nouara C Sadaoui  1 , Tatiana Ortiz  2 , Robert Dood  1 , Merve Ozcan  1   3 , Danielle M Herder  1 , Monika Haemmerle  1 , Kshipra M Gharpure  1 , Rajesha Rupaimoole  1 , Rebecca A Previs  1 , Sherry Y Wu  1 , Sunila Pradeep  1 , Xiaoyun Xu  4 , Hee Dong Han  1 , Behrouz Zand  1 , Heather J Dalton  1 , Morgan Taylor  1 , Wei Hu  1 , Justin Bottsford-Miller  1 , Myrthala Moreno-Smith  1 , Yu Kang  1 , Lingegowda S Mangala  1 , Cristian Rodriguez-Aguayo  5 , Vasudha Sehgal  6 , Erika L Spaeth  7 , Prahlad T Ram  6 , Stephen T C Wong  4   8 , Frank C Marini  9 , Gabriel Lopez-Berestein  5   10 , Steve W Cole  11 , Susan K Lutgendorf  12   13   14 , Mariella De Biasi  15 , Anil K Sood  16   10   17
Affiliations

Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction

Julie K Allen et al. Cancer Res. .

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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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Sustained adrenergic signaling increases nerve counts in tumors
(a) Neurofilament expression in orthotopic SKOV3ip1 tumors in control and mice exposed to restraint stress. (b) Nerve counts in orthotopic SKOV3ip1 and HeyA8 tumors. (c) norepinephrine (NE) levels in SKOV3ip1 tumors and correlation with nerve counts within the tumors. (d–e) Tumor growth and nerve counts in SKOV3ip1 tumors exposed to hexamethonium bromide and restraint stress. (f–g) Tumor growth and nerve counts in sham and adrenalectomized mice exposed to restraint stress. Results represent the mean ± s.e.m.; n = 10 mice per group. *P < 0.05. Scale bar represents 50 μM.
Figure 2
Figure 2. NE induced BDNF expression
(a) Network map of upregulated genes involved in neuronal growth and function. Relative expression levels of BDNF in (b) NE-treated cells with non-specific and specific ADRB blockers. (c) after treatment with NE, Iso, or ADRB3-specific agonist, (d) after treatment with forskolin, (e) after treatment with Brefeldin A (Epac antagonist) or 8CPT-2Me-cAMP (Epac agonist), (f) after treatment with SP600125 (Jnk antagonist) and NE. BDNF promoter activity after treatment with (g) NE or (h) NE and SP600125 (Jnk antagonist) or NE and SR59230A (ADRB3 blocker). *P < 0.05
Figure 3
Figure 3. Increased nerve counts are driven by BDNF induction
(a) Tumor weight in restraint-stress orthotropic mouse model with control or BDNF siRNA-DOPC. (b) Nerve counts of tumors in each group in the SKOV3ip1 model. (c) Intra-tumoral norepinephrine (NE) levels in each group in the SKOV3ip1 model. (d) Tumor weight in restraint stress orthotopic models treated with control or BDNF-DOPC siRNA. (e) Nerve counts of tumors in each group in the HeyA8 model. (f) Tumor weight in restraint stress orthotopic RKO colon cancer model. (g) Nerve counts of tumors in each group in the RKO model. (h) Tumor weight in control and BDNF overexpressing SKOV3ip1 model. (i) Nerve counts of tumors in each group. Means and standard error of the mean are shown. N = 10 mice per group. * P <0.05. Scale bar represents 50 μM.
Figure 4
Figure 4. Adrenergic-mediated mTrkB activation leads to increased tumor growth and nerve counts
(a) Tumor weight in restraint stress orthotopic SKOV3ip1 models treated with control or hTrkb siRNA-DOPC. (b) Nerve counts of tumors in each group in the hTrkb siRNA SKOV3ip1 model. (c) Tumor weight in restraint stress orthotopic SKOV3ip1 mouse models treated with control or mTrkB siRNA-chitosan. (d) Nerve counts of tumors in each group in the mTrkB siRNA SKOV3ip1 model. (e) Tumor weight in restraint stress +/+TrkBF616A mouse models treated with vehicle or 1NaPP1. (f) Nerve counts of tumors in each group in the ID8-VEGF tumor-bearing +/+TrkBF616A mouse model. Means and standard error of the mean are shown; n = 10 mice per group. *P < 0.05. Scale bar represents 50 μM.
Figure 5
Figure 5. High BDNF expression and tumor nerve counts correlate with poor outcome in ovarian cancer patients
(a) BDNF expression in human ovarian tumors and Kaplan-Meier curves of disease-specific survival in patients with epithelial ovarian carcinoma (n = 108) with high or low BDNF expression. (b) Nerve counts in human ovarian tumors and Kaplan-Meier curves of disease-specific survival in patients with epithelial ovarian carcinoma (n = 108) with high or low nerve counts. (c–d) Correlation of intratumoral NE levels in human ovarian tumor samples with BNDF and nerve counts. Scale bar represents 50 μM.
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