ECE2016 Oral Communications Thyroid Cancer (5 abstracts)
Complex immunometabolic pathways mediate the interaction between thyroid carcinoma cells and tumor-associated macrophages
Rob Arts 1 , Theo Plantinga 2 , Bas Heinhuis 1 , Sander Tuit 4 , Mirela Petrulea 3 , Marika Tesselaar 2 , Yvette Sloot 1 , Benno Kusters 2 , Leo Joosten 1 , Carmen Georgescu 3 , Johannes Smit 1 , Mihai Netea 1 , Joakim Schulze 4 & Romana Netea-Maier 1
1Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; 2Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands; 3Department of Endocrinology, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; 4Genomics and Immunoregulation, LIMES, University of Bonn, Bonn, Romania.
Background: Tumor-associated macrophages (TAMs) with dysregulated inflammatory phenotypes play a key role in carcinogenesis. In thyroid carcinoma (TC), excessive release of proinflammatory cytokines decreases the expression of sodium-iodine transporter and inflammation potentiates tumor progression.
Aim: To assess the impact of TC cells on the functional reprograming of TC-induced macrophages at the level of transcriptome and metabolic pathways, and assess their influence on the proinflammatory phenotype of TAMs.
Methods: TC cell lines TPC1, BC-PAP and FTC133 were co-incubated with human monocytes in a trans-well system. Release of cytokines and transcriptomics profiles of the immune cells and of the TC cell lines were investigated. The metabolic reprogramming was validated by metabolite assessment, perturbation experiments, and immunohistochemical (IHC) assessment of metabolic enzymes in TAMs in TC tissue samples.
Results: Co-incubation of TC cells with monocytes and stimulation of monocytes with TC-conditioned medium resulted in differentiation of TC-induced macrophages with a strong proinflammatory profile producing 3- to 5-fold more proinflammatory cytokines (TNF, IL–6) and chemokines (IL–8) than control macrophages. Metabolite assessment and perturbation experiments revealed a central role for lactate-mediated effects. Transcriptome profiling of TC-induced macrophages identified strongly upregulated metabolic pathways e.g. glycolysis. This was confirmed by IHC staining of glycolytic enzymes and receptors (PFKFB3, PKM2, lactate receptor) in TAMs in TC tissue and by an increased maximal extracellular acidification rate of TC-induced macrophages. Inhibition of mTOR reversed the upregulation of cytokine production which was partially dependent on epigenetic histone modifications (H3K4me3) at the promoter sites of IL6 and TNFα.To support the role of mTOR pathway we investigated SNPs in PI3K, Akt, and mTOR in two separate cohorts of TC patients. Akt1 SNP rs3803304, resulting in increased phosphorylation of Akt, was more prevalent in TC patients.
Conclusion: Transcriptional regulatory nodes involving metabolic pathways e.g. aerobic glycolysis regulate the interplay between TC cells and TAM, resulting in a microenvironment with a strong inflammatory profile. These pathways represent potential therapeutic targets in TC.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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