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. .
Multiple studies suggest that chronic stress accelerates the growth of existing tumors by activating the sympathetic nervous system. Data suggest that sustained adrenergic signaling can induce tumor growth, secretion of pro-inflammatory cytokines, and macrophage infiltration. Our goal was to study the role of adrenergic-stimulated macrophages in ovarian cancer biology. Cytokine arrays were used to assess the effect of adrenergic stimulation in pro-tumoral cytokine networks. An orthotopic model of ovarian cancer was used to assess the in vivo effect of daily restraint stress on tumor growth and adrenergic-induced macrophages. Cytokine analyses showed that adrenergic stimulation modulated pro-inflammatory cytokine secretion in a SKOV3ip1 ovarian cancer cell/U937 macrophage co-culture system. Among these, platelet-derived growth factor AA (PDGF-AA), epithelial cell-derived neutrophil-activating peptide (ENA-78), Angiogenin, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-5 (IL-5), Lipocalin-2, macrophage migration inhibitory factor (MIF), and transferrin receptor (TfR) were upregulated. Enriched biological processes included cytokine-mediated signaling pathways and positive regulation of cell proliferation. In addition, daily restraint stress increased ovarian cancer growth, infiltration of CD68+ macrophages, and expression of PDGF-AA in orthotopic models of ovarian cancer (SKOV3ip1 and HeyT30), while zoledronic acid, a macrophage-depleting agent, abrogated this effect. Furthermore, in ovarian cancer patients, high PDGFA expression correlated with worse outcomes. Here, it is shown that the adrenergic regulation of macrophages and PDGFA might play a role in ovarian cancer progression.
La interacción entre la mente y el cerebro es un tema de gran interés y relevancia en el campo de la salud mental. La comprensión de cómo funciona el cerebro y cómo influye en nuestros pensamientos, emociones y comportamientos puede ayudarnos a desarrollar tratamientos más efectivos y personalizados para diversos trastornos mentales, como la depresión, la ansiedad, el trastorno bipolar y otros.
Work from our group and others suggest that chronic stress accelerates growth of existing tumors by activating the sympathetic nervous system. Specifically, our data suggest that sustained adrenergic signaling can induce tumor growth, secretion of pro-inflammatory cytokines and macrophage infiltration. Moreover, increased macrophage infiltration was associated with decreased survival in ovarian cancer patients. Hence, we investigated role of adrenergic-stimulated macrophages in ovarian cancer biology. To assess the effect of adrenergic stimulation in pro-tumoral functional outputs, we used cytokine arrays and invasion assays. A pre-clinical orthotopic model of ovarian cancer was used to assess the in vivo effect of daily restraint stress on tumor growth and adrenergic-induced macrophages. Cytokine array analyses showed that adrenergic stimulation modulated pro-inflammatory cytokine secretion in a SKOV3ip1 (ovarian cancer cells) /U937 (macrophages) co-culture system. Among these, 23 significantly upregulated cytokines were identified in both, epinephrine and norepinephrine, treated co-culture systems. PDGF-AA, ENA-78, Angiogenin, VEGF, GM-CSF, IL-5, Lipocalin-2, MIF, and TfR were among upregulated cytokines shared between treatment groups. In addition, daily restraint stress resulted in increased ovarian cancer growth and infiltration of CD68+ macrophages in two orthotopic models of ovarian cancer (SKOV3ip1 and HeyA8), while zoledronic acid (a bisphosphonate that has been shown to impair macrophage activity) abrogated this effect. Immunohistochemistry analyses showed restraint stress increased expression of PDGF-AA and ENA-78 inflammatory cytokines. Here, we show that adrenergic regulation of macrophages might play a key role in the progression of ovarian cancer. Citation Format: Claudia B. Colon-Echevarria, Tatiana Ortiz, Lizette Maldonado-Laboy, Melanie J. Hidalgo-Vargas, Alexandra N. Aquino, Guillermo N. Armaiz-Pena. Adrenergic modulation of inflammatory cytokines in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 512.
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