Abstract 512: Adrenergic modulation of inflammatory cytokines in ovarian cancer

Abstract

Abstract 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.