Modulation of double-stranded RNA pattern recognition receptor signaling in ovarian cancer cells promotes inflammatory queues

// Maria Muccioli 1, 2 , Harika Nandigam 1, 5 , Tiffany Loftus 1 , Manindra Singh 1, 2 , Amritha Venkatesh 1, 5 , Julia Wright 1 , Michelle Pate 1 , Kelly McCall 2, 3, 4, 5, 6 and Fabian Benencia 1, 2, 4, 5, 6 1 Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA 2 Interdisciplinary Graduate Program in Molecular and Cellular Biology, Ohio University, Athens, OH, 45701, USA 3 Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, 45701, USA 4 Diabetes Institute at Ohio University, Ohio University, Athens, OH, 45701, USA 5 Biomedical Engineering Program, Russ College of Engineering & Technology, Ohio University, Athens, OH, 45701, USA 6 Translational Biomedical Sciences Doctoral Program, Ohio University, Athens, OH, 45701, USA Correspondence to: Fabian Benencia, email: benencia@ohio.edu Keywords: ovarian cancer; dendritic cells; dsRNA; PRR; chemokines Received: June 19, 2018      Accepted: October 24, 2018      Published: November 30, 2018 ABSTRACT Inflammation and cancer are inter-related, and both pro- and anti-tumorigenic effects are possible in different contexts, highlighting the importance of characterizing specific inflammatory pathways in distinct tumor types. Malignant cells and non-cancerous cells such as fibroblasts, infiltrating leukocytes (i.e., dendritic cells [DC], macrophages, or lymphocytes) and endothelial cells, in combination with the extracellular matrix, constitute the tumor microenvironment (TME). In the last decades, the role of the TME in cancer progression has gained increased attention and efforts directed at abrogating its deleterious effects on anti-cancer therapies have been ongoing. In this context, we investigated the potential of mouse and human ovarian cancer cells to produce inflammatory factors in response to pathogen recognition receptor (PRR) signaling, which might help to shape the biology of the TME. We determined that mouse ovarian tumors generate chemokines that are able to interact with receptors harbored by tumor-associated DCs. We also found that dsRNA triggers significant pro-inflammatory cytokine up-regulation in both human and mouse ovarian tumor cell lines, and that several PRR can simultaneously contribute to the stimulated inflammatory response displayed by these cells. Thus, dsRNA-activated PRRs may not only constitute potentially relevant drug targets for therapies aiming to prevent inflammation associated with leukocyte recruitment, or as co-adjuvants of therapeutic treatments, but also might have a role in development of nascent tumors, for example via activation of cancer cells by microbial molecules associated to pathogens, or with those appearing in circulation due to dysbiosis.