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Aryl hydrocarbon receptor ligands in cancer: friend and foe

Key Points

  • The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; commonly referred to as 'dioxin').

  • Three distinct classes of ligands bind to AHR: agonists, antagonists and selective AHR modulators. AHR is activated by endogenous ligands such as kynurenine, kynurenic acid and indoxyl sulphate, and physiologically relevant flora can produce potent AHR ligands from tryptophan.

  • Human AHR and mouse AHR exhibit substantial differences in ligand specificity, which might influence the progression of cancer. This complicates the validity of mouse models for studying the effects of AHR on human carcinogenesis.

  • Numerous studies demonstrate the ability of AHR to increase the proliferative and migratory potential of tumour cells.

  • AHR directly modulates inflammatory signalling, and AHR levels are often increased in tumours, probably as a result of inflammatory signalling. AHR agonist-mediated activity can have a key role in the production of regulatory T cells and thus could have a role in immune tolerance in cancer.

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as 'dioxin'. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours.

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Figure 1: Agonist-mediated activation of AHR.
Figure 2: AHR activity within the tumour microenvironment.
Figure 3: Proposed mechanisms of cell cycle modulation by AHR.
Figure 4: Proposed role of AHR in tumour metastasis.

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Acknowledgements

The authors would like to thank M. H. Perdew for critically reviewing the manuscript. The authors apologize to those whose work is not cited owing to space limitations. The authors' research is funded by US National Institutes of Health grants (ES004869, ES019964 and ES022186).

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Glossary

2,3,7,8-tetrachlorodibenzo-p-dioxin

(TCDD). A polycyclic halogenated hydrocarbon that is highly toxic to rodents and that exhibits high affinity for the aryl hydrocarbon receptor.

Polycyclic aromatic hydrocarbons

A group of more than 100 different stable organic molecules comprised of only carbon and hydrogen. They are large, planar molecules assembled from a collection of fused benzene-like rings. They are formed during the incomplete burning of coal, oil, gas, garbage or other organic substances such as tobacco or charbroiled meat.

Barrier function

The integrity of a protective epithelial layer that serves as a barrier and allows selective absorption.

Antagonists

In the context of this Review, aryl hydrocarbon receptor (AHR) ligands that inhibit canonical dioxin-responsive element (DRE)-mediated and non-DRE-mediated AHR activity.

TRAMP

(Transgenic adenocarcinoma of mouse prostate). A mouse prostate cancer model in which mice that express SV40 T/t antigens that are under the control of the androgen-sensitive rat probasin promoter develop focal adenocarcinomas with 100% frequency between 10 and 20 weeks of age.

Epithelial–mesenchymal transition

The process by which cells convert from an epithelial to a mesenchymal phenotype. This process, which occurs during normal embryonic development, can be abnormally activated in carcinomas, resulting in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Weak agonist

In the context of this Review, this refers to an aryl hydrocarbon receptor ligand that displays partial agonist activity, eliciting a sub-maximal dioxin-responsive element-mediated transcriptional response. In addition, in the presence of a strong agonist, a weak agonist will exhibit antagonist activity.

Selective AHR modulators

(SAHRMs). Aryl hydrocarbon receptor (AHR) ligands that display functional selectivity, exhibiting negligible dioxin-responsive element (DRE)-mediated transcriptional responses while maximally stimulating non-DRE mediated AHR activity.

Full agonist

In the context of this Review, an aryl hydrocarbon receptor ligand that maximally elicits canonical dioxin-responsive element-mediated transcriptional responses.

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Murray, I., Patterson, A. & Perdew, G. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 14, 801–814 (2014). https://doi.org/10.1038/nrc3846

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