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How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 September 2020) | Viewed by 59946

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Special Issue Editor

Prof. David Sherr

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Guest Editor

Boston University School of Public Health, Boston, MA, USA
Interests: the role of the AHR in cancer aggression and immunosuppression; the AHR as an immune checkpoint

Special Issue Information

Dear Colleagues,

The purpose of this Special Issue is to map the trajectory of the AHR from a toxicological oddity to a therapeutic target, with an emphasis on immuno-oncology and autoimmunity. The overarching theme is to reinforce the idea that all basic molecular science is translational science—it just takes time to develop. We will track: (1) the early days of the AHR when mouse genetics suggested a specific mediator of dioxin activity, (2) the cloning of the AHR which enabled scientists to have a “handle” on an important gene and protein, (3) the definition of some of the AHR’s molecular attributes, (4) the association of the AHR with “normal” biological function, (5) the identification of endogenous and microbial ligands that may effect different AHR-mediated outcomes, and (6) the emerging approaches of targeting the AHR for treatment of cancer, autoimmunity, and potentially other diseases. The Special Issue “How the AHR Became Important—A Lesson in How Basic Science Leads to Actionable Translational Medicine” will include historic reviews of the molecular science behind the AHR and original articles.

Prof. David Sherr
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

aryl hydrocarbon receptor (AHR/AhR)
immune checkpoints
immuno-oncology
immunotoxicology
cancer
autoimmunity
AHR modulators

Published Papers (13 papers)

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Research

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18 pages, 2680 KiB

Open AccessArticle

AhR Activation Leads to Alterations in the Gut Microbiome with Consequent Effect on Induction of Myeloid Derived Suppressor Cells in a CXCR2-Dependent Manner

by Wurood Hantoosh Neamah, Philip Brandon Busbee, Hasan Alghetaa, Osama A. Abdulla, Mitzi Nagarkatti and Prakash Nagarkatti

Int. J. Mol. Sci. 2020, 21(24), 9613; https://doi.org/10.3390/ijms21249613 - 17 Dec 2020

Cited by 25 | Viewed by 2502

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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18 pages, 4250 KiB

Open AccessArticle

AHR Signaling Interacting with Nutritional Factors Regulating the Expression of Markers in Vascular Inflammation and Atherogenesis

by Carla Dahlem, Sarah Y. Kado, Yi He, Keith Bein, Dalei Wu, Thomas Haarmann-Stemmann, Norman Y. Kado and Christoph F. A. Vogel

Int. J. Mol. Sci. 2020, 21(21), 8287; https://doi.org/10.3390/ijms21218287 - 05 Nov 2020

Cited by 14 | Viewed by 3231

Abstract

There is strong evidence that exposure to fine particulate matter (PM_2.5) and a high-fat diet (HFD) increase the risk of mortality from atherosclerotic cardiovascular diseases. Recent studies indicate that PM_2.5 generated by combustion activates the Aryl Hydrocarbon Receptor (AHR) and inflammatory cytokines contributing to PM_2.5-mediated atherogenesis. Here we investigate the effects of components of a HFD on PM-mediated activation of AHR in macrophages. Cells were treated with components of a HFD and AHR-activating PM and the expression of biomarkers of vascular inflammation was analyzed. The results show that glucose and triglyceride increase AHR-activity and PM_2.5-mediated induction of cytochrome P450 (CYP)1A1 mRNA in macrophages. Cholesterol, fructose, and palmitic acid increased the PM- and AHR-mediated induction of proinflammatory cytokines in macrophages. Treatment with palmitic acid significantly increased the expression of inflammatory cytokines and markers of vascular injury in human aortic endothelial cells (HAEC) after treatment with PM_2.5. The PM_2.5-mediated activation of the atherogenic markers C-reactive protein (CRP) and S100A9, a damage-associated molecular pattern molecule, was found to be AHR-dependent and involved protein kinase A (PKA) and a CCAAT/enhancer-binding protein (C/EBP) binding element. This study identified nutritional factors interacting with AHR signaling and contributing to PM_2.5-induced markers of atherogenesis and future cardiovascular risk. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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20 pages, 3144 KiB

Open AccessArticle

Dietary AhR Ligands Regulate AhRR Expression in Intestinal Immune Cells and Intestinal Microbiota Composition

by Oliver Schanz, Rieka Chijiiwa, Sevgi Can Cengiz, Yasmin Majlesain, Heike Weighardt, Haruko Takeyama and Irmgard Förster

Int. J. Mol. Sci. 2020, 21(9), 3189; https://doi.org/10.3390/ijms21093189 - 30 Apr 2020

Cited by 37 | Viewed by 4843

Abstract

A diet rich in vegetables and fruit is generally considered healthy because of a high content of phytochemicals, vitamins, and fiber. The phytochemical indole-3-carbinol (I3C), a derivative of glucobrassicin, is sold as a dietary supplement promising diverse health benefits. I3C metabolites act as ligands of the aryl hydrocarbon receptor (AhR), an important sensor for environmental polyaromatic chemicals. Here, we investigated how dietary AhR ligand supplementation influences AhR target gene expression and intestinal microbiota composition. For this, we used AhR repressor (AhRR)-reporter mice as a tool to study AhR activation in the intestine following dietary I3C-supplementation in comparison with AhR ligand-deprived diets, including a high fat diet. AhRR expression in intestinal immune cells was mainly driven by dietary AhR ligands and was independent of microbial metabolites. A lack of dietary AhR ligands caused enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis and correlated with the expansion of Enterobacteriaceae, whereas Clostridiales, Muribaculaceae, and Rikenellaceae were strongly reduced. I3C supplementation largely reverted this effect. Comparison of I3C-induced changes in microbiota composition using wild-type (WT), AhRR-deficient, and AhR-deficient mice revealed both AhR-dependent and -independent alterations in the microbiome. Overall, our study demonstrates that dietary AhR ligand supplementation has a profound influence on Ahrr expression in intestinal immune cells as well as microbiota composition. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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Review

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15 pages, 1575 KiB

Open AccessReview

Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor—A Personal Perspective on Thymus and Skin

by Charlotte Esser

Int. J. Mol. Sci. 2021, 22(4), 1844; https://doi.org/10.3390/ijms22041844 - 12 Feb 2021

Cited by 3 | Viewed by 1827

Abstract

Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even “paradigmatic”, shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor “aryl hydrocarbon receptor” (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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22 pages, 4193 KiB

Open AccessReview

AhR and Cancer: From Gene Profiling to Targeted Therapy

by Anaïs Paris, Nina Tardif, Marie-Dominique Galibert and Sébastien Corre

Int. J. Mol. Sci. 2021, 22(2), 752; https://doi.org/10.3390/ijms22020752 - 13 Jan 2021

Cited by 40 | Viewed by 5195

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has been shown to be an essential regulator of a broad spectrum of biological activities required for maintaining the body’s vital functions. AhR also plays a critical role in tumorigenesis. Its role in cancer is complex, encompassing both pro- and anti-tumorigenic activities. Its level of expression and activity are specific to each tumor and patient, increasing the difficulty of understanding the activating or inhibiting roles of AhR ligands. We explored the role of AhR in tumor cell lines and patients using genomic data sets and discuss the extent to which AhR can be considered as a therapeutic target. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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22 pages, 2709 KiB

Open AccessReview

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

by Zhongyan Wang, Megan Snyder, Jessica E. Kenison, Kangkang Yang, Brian Lara, Emily Lydell, Kawtar Bennani, Olga Novikov, Anthony Federico, Stefano Monti and David H. Sherr

Int. J. Mol. Sci. 2021, 22(1), 387; https://doi.org/10.3390/ijms22010387 - 31 Dec 2020

Cited by 50 | Viewed by 7223

Abstract

For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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13 pages, 486 KiB

Open AccessReview

The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands

by Nathaniel G. Girer, Craig R. Tomlinson and Cornelis J. Elferink

Int. J. Mol. Sci. 2021, 22(1), 49; https://doi.org/10.3390/ijms22010049 - 23 Dec 2020

Cited by 19 | Viewed by 4275

Abstract

The aryl hydrocarbon receptor (AHR) has been studied for over 40 years, yet our understanding of this ligand-activated transcription factor remains incomplete. Each year, novel findings continually force us to rethink the role of the AHR in mammalian biology. The AHR has historically been studied within the context of potent activation via AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with a focus on how the AHR mediates TCDD toxicity. Research has subsequently revealed that the AHR is actively involved in distinct physiological processes ranging from the development of the liver and reproductive organs, to immune system function and wound healing. More recently, the AHR was implicated in the regulation of energy metabolism and is currently being investigated as a potential therapeutic target for obesity. In this review, we re-trace the steps through which the early toxicological studies of TCDD led to the conceptual framework for the AHR as a potential therapeutic target in metabolic disease. We additionally discuss the key discoveries that have been made concerning the role of the AHR in energy metabolism, as well as the current and future directions of the field. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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19 pages, 18304 KiB

Open AccessReview

How Ah Receptor Ligand Specificity Became Important in Understanding Its Physiological Function

by Iain A. Murray and Gary H. Perdew

Int. J. Mol. Sci. 2020, 21(24), 9614; https://doi.org/10.3390/ijms21249614 - 17 Dec 2020

Cited by 24 | Viewed by 4776

Abstract

Increasingly, the aryl hydrocarbon receptor (AHR) is being recognized as a sensor for endogenous and pseudo-endogenous metabolites, and in particular microbiota and host generated tryptophan metabolites. One proposed explanation for this is the role of the AHR in innate immune signaling within barrier tissues in response to the presence of microorganisms. A number of cytokine/chemokine genes exhibit a combinatorial increase in transcription upon toll-like receptors and AHR activation, supporting this concept. The AHR also plays a role in the enhanced differentiation of intestinal and dermal epithelium leading to improved barrier function. Importantly, from an evolutionary perspective many of these tryptophan metabolites exhibit greater activation potential for the human AHR when compared to the rodent AHR. These observations underscore the importance of the AHR in barrier tissues and may lead to pharmacologic therapeutic intervention. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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14 pages, 6696 KiB

Open AccessReview

From Suppressor T Cells to Regulatory T Cells: How the Journey that Began with the Discovery of the Toxic Effects of TCDD Led to Better Understanding of the Role of AhR in Immunoregulation

by Narendra Prasad Singh, Mitzi Nagarkatti and Prakash Nagarkatti

Int. J. Mol. Sci. 2020, 21(21), 7849; https://doi.org/10.3390/ijms21217849 - 22 Oct 2020

Cited by 22 | Viewed by 2739

Abstract

Aryl hydrocarbon receptor (AhR) was identified in the early 1970s as a receptor for the ubiquitous environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), which is a member of halogenated aromatic hydrocarbons (HAHs). TCDD was found to be highly toxic to the immune system, causing thymic involution and suppression of a variety of T and B cell responses. The fact that environmental chemicals cause immunosuppression led to the emergence of a new field, immunotoxicology. While studies carried out in early 1980s demonstrated that TCDD induces suppressor T cells that attenuate the immune response to antigens, further studies on these cells were abandoned due to a lack of specific markers to identify such cells. Thus, it was not until 2001 when FoxP3 was identified as a master regulator of Regulatory T cells (Tregs) that the effect of AhR activation on immunoregulation was rekindled. The more recent research on AhR has led to the emergence of AhR as not only an environmental sensor but also as a key regulator of immune response, especially the differentiation of Tregs vs. Th17 cells, by a variety of endogenous, microbial, dietary, and environmental ligands. This review not only discusses how the role of AhR emerged from it being an environmental sensor to become a key immunoregulator, but also confers the identification of new AhR ligands, which are providing novel insights into the mechanisms of Treg vs. Th17 differentiation. Lastly, we discuss how AhR ligands can trigger epigenetic pathways, which may provide new opportunities to regulate inflammation and treat autoimmune diseases. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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16 pages, 1671 KiB

Open AccessReview

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

by Stephen Safe, Un-ho Jin, Hyejin Park, Robert S. Chapkin and Arul Jayaraman

Int. J. Mol. Sci. 2020, 21(18), 6654; https://doi.org/10.3390/ijms21186654 - 11 Sep 2020

Cited by 67 | Viewed by 7945

Abstract

The aryl hydrocarbon receptor (AhR) was first identified as the intracellular protein that bound and mediated the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) and dioxin-like compounds (DLCs). Subsequent studies show that the AhR plays an important role in maintaining cellular homeostasis and in pathophysiology, and there is increasing evidence that the AhR is an important drug target. The AhR binds structurally diverse compounds, including pharmaceuticals, phytochemicals and endogenous biochemicals, some of which may serve as endogenous ligands. Classification of DLCs and non-DLCs based on their persistence (metabolism), toxicities, binding to wild-type/mutant AhR and structural similarities have been reported. This review provides data suggesting that ligands for the AhR are selective AhR modulators (SAhRMs) that exhibit tissue/cell-specific AhR agonist and antagonist activities, and that their functional diversity is similar to selective receptor modulators that target steroid hormone and other nuclear receptors. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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19 pages, 1235 KiB

Open AccessReview

How the AHR Became Important in Intestinal Homeostasis—A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology

by Agneta Rannug

Int. J. Mol. Sci. 2020, 21(16), 5681; https://doi.org/10.3390/ijms21165681 - 08 Aug 2020

Cited by 40 | Viewed by 5491

Abstract

Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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17 pages, 1309 KiB

Open AccessReview

Aryl Hydrocarbon Receptor Connects Inflammation to Breast Cancer

by Tiziana Guarnieri

Int. J. Mol. Sci. 2020, 21(15), 5264; https://doi.org/10.3390/ijms21155264 - 24 Jul 2020

Cited by 29 | Viewed by 4127

Abstract

Aryl hydrocarbon receptor (AhR), an evolutionary conserved transcription factor, is a pleiotropic signal transductor. Thanks to its promiscuous ligand binding domain, during the evolution of eukaryotic cells its developmental functions were integrated with biosensor functions. Its activation by a multitude of endogenous and exogenous molecules stimulates its participation in several pathways, some of which are linked to inflammation and breast cancer (BC). Over time, the study of this malignancy has led to the identification of several therapeutic targets in cancer cells. An intense area of study is dedicated to BC phenotypes lacking adequate targets. In this context, due to its high constitutive activation in BC, AhR is currently gaining more and more attention. In this review, I have considered its interactions with: 1. the immune system, whose dysregulation is a renowned cancer hallmark; 2. interleukin 6 (IL6) which is a pivotal inflammatory marker and is closely correlated to breast cancer risk; 3. NF-kB, another evolutionary conserved transcription factor, which plays a key role in immunoregulatory functions, inflammatory response and breast carcinogenesis; 4. kynurenine, a tryptophan-derived ligand that activates and bridges AhR to chronic inflammation and breast carcinogenesis. Overall, the data here presented form an interesting framework where AhR is an interesting connector between inflammation and BC. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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14 pages, 1311 KiB

Open AccessReview

The Role of Aryl Hydrocarbon Receptor (AhR) in Brain Tumors

by Maria L. Perepechaeva and Alevtina Y. Grishanova

Int. J. Mol. Sci. 2020, 21(8), 2863; https://doi.org/10.3390/ijms21082863 - 20 Apr 2020

Cited by 13 | Viewed by 4904

Abstract

Primary brain tumors, both malignant and benign, are diagnosed in adults at an incidence rate of approximately 23 people per 100 thousand. The role of AhR in carcinogenesis has been a subject of debate, given that this protein may act as either an oncogenic protein or a tumor suppressor in different cell types and contexts. Lately, there is growing evidence that aryl hydrocarbon receptor (AhR) plays an important part in the development of brain tumors. The role of AhR in brain tumors is complicated, depending on the type of tumor, on ligands that activate AhR, and other features of the pathological process. In this review, we summarize current knowledge about AhR in relation to brain tumors and provide an overview of AhR’s potential as a therapeutic target. Full article

(This article belongs to the Special Issue How the AHR Became Important-A Lesson in How Basic Science Leads to Actionable Translational Medicine)

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