Aryl hydrocarbon receptor acts as a tumor suppressor in a syngeneic MC38 colon carcinoma tumor model
Authors Yakkundi P, Gonsalves E, Galou-Lameyer M, Selby MJ, Chan WK
Received 28 November 2018
Accepted for publication 18 February 2019
Published 10 April 2019 Volume 2019:7 Pages 1—16
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Amy Norman
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Dörthe Katschinski
Poonam Yakkundi,1 Eleanor Gonsalves,1 Maria Galou-Lameyer,1 Mark J Selby,2 William K Chan3
1Animal Biology Group, Bristol-Myers Squibb Company, Redwood City, CA, 94063, USA; 2Immuno-Oncology Group, Bristol-Myers Squibb Company, Redwood City, CA, 94063, USA; 3Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA, 95211, USA
Background: Aryl hydrocarbon receptor (AHR), commonly known as an environmental sensor involved in the metabolism and elimination of xenobiotic substances, is also an important modulator in the development and functioning of the immune system. AHR expression is varied in the T cell subsets with the highest expression in T-helper 17 and T regulatory cells. It has been reported that AHR can act as a tumor promoter or a tumor suppressor, depending on the tumor type.
Methods: In an effort to understand the role played by AHR in tumor growth, the MC38 syngeneic colon carcinoma tumor model was used on C57BL/6 or ahr knockout (KO, -/-) mice with or without AHR antagonist (CH223191) treatment. Tumor sizes were measured, and biomarkers were quantified in tumor microenvironment and draining lymph nodes using flow cytometry. Enzyme-linked immunosorbent assay was used to determine the amount of cytokines in tumors.
Results: In ahr deficient mice, MC38 tumors progress more rapidly than in wild-type mice, accompanied by an increase in tumor-associated macrophages and M2 macrophages and a decrease in CD8a positive cytotoxic lymphocytes. Analysis of cytokines in the tumor microenvironment reveals a pro-inflammatory phenotype. Similar changes were observed by pharmacologic blockade of the receptor using CH223191.
Conclusion: AHR acts as a tumor suppressor in mice implanted with MC38 colon carcinoma cells as evidenced by either a blockade or deficiency of AHR.
Keywords: aryl hydrocarbon receptor, MC38, colon carcinoma, syngeneic, tumor suppressor, AHR deficiency
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