Session 5: Sylvester O'Halloran Prize Session
AB073. Attenuation of pathogenic pro-inflammatory signals in colorectal cancer via an NR4A1 agonist cytosporone B
Mohamed Ismaiel1,2, Brenda Murphy1,2, Sarah Aldhafiri2, Hugh Giffney2, Ciara Keogh2, Mukhopadhya Anindya2, Sarinj Fattah2, Kevin Thornton2, Eoin Cummins2, Helen Mohan1,2, David Brayden2, Evelyn Murphy2, Alan Baird2, Daniel Crean2, Des Winter1,2
1Department of General Surgery, St. Vincent’s University Hospital, Dublin, Ireland;2Department of School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin, Ireland
Background: Colorectal cancer (CRC) is a main cause of cancer-associated mortality globally in spite of advances in treatment. Furthermore, a strong link between chronic inflammation and CRC has been established. Nuclear orphan receptor family 4, subgroup A, member 1 (NR4A1) has emerged as a key regulator of inflammatory pathways, albeit its function in CRC remains unknown.
Methods: Human colorectal tissues (normal and tumour) (n=33), omentum (n=13) and mesenteric (n=14) tissue (adjacent to the tumour tissue) was obtained from patients undergoing colorectal resection and subsequently exposed to a NR4A1 agonist [cytosporone B (Csn-B)] for 8 hrs ex vivo in a tissue culture incubator. A cytokine/chemokine array was performed examining 105 proteins associated with tumour inflammation, and subsequent to that enzyme-linked immunosorbent assay (ELISA) and qRT-PCR was used to confirm targets of interest. Moreover, ELISA data was then stratified based on patient characteristics including gender, location, and whether they had chemoradiotherapy.
Results: The additions of NR4A1 agonist Csn-B (100 µM) was efficacious in attenuating pro-inflammatory mediators in colorectal tumours. This was not global attenuation and was specific to certain targets, such as IL-8, MCP-1, IL-1β, CCL3/4 and TNFα. Mesenteric tissue exposed to Csn-B (100 µM) displayed significantly less (P<0.001) IL-1β compared to mesentery alone, while omentum tissues remained unchanged. ELISA data stratification revealed some intriguing results revealing that Csn-B affects tumour inflammatory states from patients who have not had chemoradiotherapy, and more so who are male.
Conclusions: NR4A1 agonist CsnB attenuates pathogenic pro-inflammatory mediators in CRC ex vivo.
Keywords: Colorectal cancer (CRC); nuclear orphan receptor family type 4A1 (NR4A1); cytosporone B (Csn-B); inflammation; inflammatory mediators; omentum; mesentery
doi: 10.21037/map.2020.AB073
Cite this abstract as: Ismaiel M, Murphy B, Aldhafiri S, Giffney H, Keogh C, Anindya M, Fattah S, Thornton K, Cummins E, Mohan H, Brayden D, Murphy E, Baird A, Crean D, Winter D. Attenuation of pathogenic pro-inflammatory signals in colorectal cancer via an NR4A1 agonist cytosporone B. Mesentery Peritoneum 2020;4:AB073.
