Activation, AhR

92-87-5

HFACYLZERDEVSX-UHFFFAOYSA-N

C.I. Azoic Diazo Component 112

4-(4-Aminophenyl)aniline [1,1'-Biphenyl]-4,4'-diamine (1,1'-Biphenyl)-4,4'-diamine 4,4'-Bianiline 4,4'-Biphenyldiamine 4,4'-Diamino-1,1'-biphenyl 4,4'-Diaminobiphenyl 4,4'-Diaminodiphenyl 4,4'-Diphenylenediamine 4'-Amino-[1,1'-biphenyl]-4-ylamine bencidina Benzidin C.I. Azoic Diazo Component 112 Fast Corinth Base B NSC 146476 p,p'-Bianiline p,p'-Diaminobiphenyl p-Diaminodiphenyl UN 1885

DTXSID2020137

262-12-4

NFBOHOGPQUYFRF-UHFFFAOYSA-N

Dibenzo-p-dioxin

Dibenzo[b,e][1,4]dioxin Dibenzo[1,4]dioxin dibenzo-p-dioxina dibenzo-p-dioxinne Diphenylene dioxide Oxanthrene Phenodioxin

DTXSID8020410

118-74-1

CKAPSXZOOQJIBF-UHFFFAOYSA-N

Hexachlorobenzene

(HCB Benzene, hexachloro- Anticarie Benzene, 1,2,3,4,5,6-hexachloro- Benzenehexachloride Bunt-cure Bunt-no-more Co-op Hexa Hexachlorbenzol hexaclorobenceno Julin's carbon chloride No Bunt No Bunt Liquid NSC 9243 Pentachlorophenyl chloride Perchlorobenzene Sanocide Snieciotox UN 2729 Zaprawa nasienna sneciotox 1,2,3,4,5,6-Hexachloro-benzene

DTXSID2020682

PR:000003858

PR aryl hydrocarbon receptor

GO:0070531

GO BRCA1-A complex

GO:0004874

GO aryl hydrocarbon receptor activity

GO:0017162

GO aryl hydrocarbon receptor binding

HP:0003002

HP Breast carcinoma

WIKI increased

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

2017-02-09T14:32:32

Benzidine

2016-11-29T18:42:26

Dibenzo-p-dioxin

2016-11-29T18:42:27

Polychlorinated biphenyl

2016-11-29T18:42:27

Polychlorinated dibenzofurans

2016-11-29T18:42:27

Hexachlorobenzene

2016-11-29T18:42:27

Polycyclic aromatic hydrocarbons (PAHs)

2017-02-09T15:43:00

7955

NCBI zebra danio

WCS_9031

common ecological species Gallus gallus

143350

NCBI Pagrus major

7904

NCBI Acipenser transmontanus

41871

NCBI Acipenser fulvescens

WCS_8022

common ecological species rainbow trout

8030

NCBI Salmo salar

WCS_8355

common ecological species Xenopus laevis

8296

NCBI Ambystoma mexicanum

WCS_9054

common ecological species Phasianus colchicus

WCS_93934

common ecological species Coturnix japonica

10090

NCBI mouse

10116

NCBI rat

WCS_9606

common toxicological species human

34823

NCBI Microgadus tomcod

9606

NCBI Homo sapiens

Activation, AhR

Molecular

<h3>The AHR Receptor</h3> The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) superfamily and consists of three domains: the DNA-binding domain (DBD), ligand binding domain (LBD) and transactivation domain (TAD)<a href="#cite_note-Okey2007-1">[1]</a>. Other members of this superfamily include the AHR nuclear translocator (ARNT), which acts as a dimerization partner of the AHR <a href="#cite_note-Hoffman1991-2">[2]</a><a href="#cite_note-Poland1976-3">[3]</a>; Per, a circadian transcription factor; and Sim, the “single-minded” protein involved in neuronal development <a href="#cite_note-Gu2000-4">[4]</a><a href="#cite_note-Kewley2004-5">[5]</a>. This group of proteins shares a highly conserved PAS domain and is involved in the detection of and adaptation to environmental change<a href="#cite_note-Gu2000-4">[4]</a>. Investigations of invertebrates possessing early homologs of the AhR suggest that the AhR evolutionarily functioned in regulation of the cell cycle, cellular proliferation and differentiation, and cell-to-cell communications (Hahn et al 2002). However, critical functions in angiogenesis, regulation of the immune system, neuronal processes, metabolism, development of the heart and other organ systems, and detoxification have emerged sometime in early vertebrate evolution (Duncan et al., 1998; Emmons et al., 1999; Lahvis and Bradfield, 1998). <h3>The molecular Initiating Event</h3> <div> <div><a class="image" href="/wiki/index.php/File:AHR_mechanism.jpeg"><img alt="" class="thumbimage" src="/wiki/images/thumb/6/6e/AHR_mechanism.jpeg/450px-AHR_mechanism.jpeg" style="height:331px; width:450px" /></a> <div>Figure 1: The molecular mechanism of activation of gene expression by AHR.</div> <div> </div> </div> </div> The molecular mechanism for AHR-mediated activation of gene expression is presented in Figure 1. In its unliganded form, the AHR is part of a cytosolic complex containing heat shock protein 90 (HSP90), the HSP90 co-chaperone p23 and AHR-interacting protein (AIP)<a href="#cite_note-Fujii2010-6">[6]</a>. Upon ligand binding, the AHR migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with ARNT<a href="#cite_note-Mimura2003-7">[7]</a>. The AHR-ARNT complex then binds to a xenobiotic response element (XRE) found in the promoter of an AHR-regulated gene and recruits co-regulators such as CREB binding protein/p300, steroid receptor co-activator (SRC) 1, SRC-2, SRC-3 and nuclear receptor interacting protein 1, leading to induction or repression of gene expression<a href="#cite_note-Fujii2010-6">[6]</a>. Expression levels of several genes, including phase I (e.g. cytochrome P450 (CYP) 1A, CYP1B, CYP2A) and phase II enzymes (e.g. uridine diphosphate glucuronosyl transferase (UDP-GT), glutathione S-transferases (GSTs)), as well as genes involved in cell proliferation (transforming growth factor-beta, interleukin-1 beta), cell cycle regulation (p27, jun-B) and apoptosis (Bax), are regulated through this mechanism <a href="#cite_note-Fujii2010-6">[6]</a><a href="#cite_note-Giesy2006-8">[8]</a><a href="#cite_note-Mimura2003-7">[7]</a><a href="#cite_note-Safe1994-9">[9]</a>. <h3>AHR Isoforms</h3> <ul> <li>Over time the AhR has undergone gene duplication and diversification in vertebrates, which has resulted in multiple clades of AhR, namely AhR1, AhR2, and AhR3 (Hahn 2002).</li> <li>Fishes and birds express AhR1s and AhR2s, while mammals express a single AhR that is homologous to the AhR1 (Hahn 2002; Hahn et al 2006).</li> <li>The AhR3 is poorly understood and known only from some cartilaginous fishes (Hahn 2002).</li> <li>Little is known about diversity of AhRs in reptiles and amphibians (Hahn et al 2002).</li> <li>In some taxa, subsequent genome duplication events have further led to multiple isoforms of AhRs in some species, with up to four isoforms of the AhR (α, β, δ, γ) having been identified in Atlantic salmon (Salmo salar) (Hansson et al 2004).</li> <li>Although homologs of the AhR have been identified in some invertebrates, compared to vertebrates these AhRs have differences in binding of ligands in the species investigated to date (Hahn 2002; Hahn et al 1994).</li> </ul>   Roles of isoforms in birds: Two AHR isoforms (AHR1 and AHR2) have been identified in the black-footed albatross (Phoebastria nigripes), great cormorant (Phalacrocorax carbo) and domestic chicken (Gallus gallus domesticus)<a href="#cite_note-Yasui2007-10">[10]</a>. AHR1 mRNA levels were similar in the kidney, heart, lung, spleen, brain, gonad and intestine from the great cormorant but were lower in muscle and pancreas. AHR2 expression was mainly observed in the liver, but was also detected in gonad, brain and intestine. AHR1 levels represented a greater proportion (80%) of total AHR levels than AHR2 in the cormorant liver<a href="#cite_note-Yasui2007-10">[10]</a>, and while both AHR isoforms bound to TCDD, AHR2 was less effective at inducing TCDD-dependent transactivation compared to AHR1 in black-footed albatross, great cormorant and domestic chicken<a href="#cite_note-Lee2009-11">[11]</a><a href="#cite_note-Yasui2007-10">[10]</a>. <ul> <li>AhR1 and AhR2 both bind and are activated by TCDD in vitro (Yasui et al 2007).</li> <li>AhR1 has greater binding affinity and sensitivity to activation by TCDD relative to AhR2 (Yasui et al 2007).</li> <li>AhR1 is believed to mediate toxicities of DLCs, while AhR2 has no known role in toxicities (Farmahin et al 2012; Farmahin et al 2013; Manning et al 2012).</li> </ul> Roles of isoforms in fishes: <ul> <li>AhR1 and AhR2 both bind and are activated by TCDD in vitro (Bak et al 2013; Doering et al 2014; 2015; Karchner et al 1999; 2005).</li> <li>AhR1 has greater sensitivity to activation by TCDD than AhR2 in red seabream (Pagrus major), white sturgeon (Acipenser transmontanus), and lake sturgeon (Acipenser fulvescens) (Bak et al 2013; Doering et al 2014; 2015)</li> <li>AhR2 has greater binding affinity or activation by TCDD than AhR1 in zebrafish (Danio rerio) and mummichog (Fundulus heteroclitus) (Karchner et al 1999; 2005).</li> <li>AhR2 is believed to mediate toxicities in fishes, while AhR1 has no known role in toxicities. Specifically, knockdown of AhR2 protects against toxicities of dioxin-like compounds (DLCs) and polycyclic aromatic hydrocarbons (PAHs) in zebrafish (Danio rerio) and mummichog (Fundulus heteroclitus), while knockdown of AhR1 offers no protection (Clark et al 2010; Prasch et al 2003; Van Tiem & Di Giulio 2011).</li> </ul> Roles of isoforms in amphibians and reptiles: <ul> <li>Less is known about AhRs of amphibians or reptiles.</li> <li>AhR1 is believed to mediate toxicities in amphibians (Hahn 2002; Lavine et al 2005; Oka et al 2016; Shoots et al 2015). However, all AhRs of amphibians that have been investigated have very low affinity for TCDD (Hahn 2002; Lavine et al 2005; Oka et al 2016; Shoots et al 2015).</li> <li>Both AhR1s and AhR2 of American alligator (Alligator mississippiensis) are activated by agonists with comparable sensitivities (Oka et al 2016). AhRs of no other reptiles have been investigated.</li> </ul> Role in mammals AhR expression is essentially ubiquitous in mammals consistent with a broad-spectrum homeostatic role, however expression levels varying widely across tissues with the liver, thymus, lung, kidney, spleen, and placenta exhibiting greatest expression (Harper PA). Additionally, AhR expression is developmentally regulated, and more recent evidence indicates a role for the AhR in developmental process affecting hematopoiesis, immune system biology, neural differentiation, and liver architecture (Wright E J) . AHR is involved in regulating the rate of apoptosis of oocytes in germ cell nests during embryonic life and in regulating survival of oocytes in the fetal and neonatal ovary. Specifically, studies have shown that ovaries obtained from AHRKO mice on ED13.5 and cultured for 72 h in the absence of hormonal support with the aim of inducing apoptosis, contained higher numbers of non-apoptotic germ cells compared to wild-type (WT) ovaries cultured in the same conditions (Hernández-Ochoa)

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? <h3>Transactivation Reporter Gene Assays (recommended approach)</h3> <h4>Transient transfection transactivation</h4> Transient transfection transactivation is the most common method for evaluating nuclear receptor activation<a href="#cite_note-Raucy2010-12">[12]</a>. Full-length AHR cDNAs are cloned into an expression vector along with a reporter gene construct (chimeric luciferase, P-lactamase or CAT reporter vectors containing the appropriate response elements for the gene of interest). There are a number of commercially available cell lines that can serve as recipients for these vectors (CV-1, HuH7, FLC-7, LS174T, LS180 MCF-7, HEC1, LLC-PK1, HEK293, HepG2, and Caco-2 cells)<a href="#cite_note-Raucy2010-12">[12]</a>. The greatest advantage of using transfected cells, rather than primary cell cultures, is the assurance that the nuclear receptor of interest is responsible for the observed induction. This would not be possible in a primary cell culture due to the co-regulation of different receptors for the same target genes. This model makes it easy to compare the responsiveness of the AHR across multiple species under the same conditions simply by switching out the AHR clone. One disadvantage to the transient transfection assay is the inherent variability associated with transfection efficiency, leading to a movement towards the use of stable cell lines containing the nuclear receptor and reporter gene linked to the appropriate response elements<a href="#cite_note-Raucy2010-12">[12]</a>. <h5>Luciferase reporter gene (LRG) assay</h5> The described luciferase reporter gene (LRG) assays have been used to investigate activation of AhRs of: <ul> <li>Humans (Homo sapiens) (Abnet et al 1999) </li> <li>Species of birds, namely chicken (Gallus gallus), ring-necked pheasant (Phasianus colchicus), Japanese quail (Coturnix japonica), and common tern (Sterna hirundo) (Farmahin et al 2012; Manning et al 2013), Mutant AhR1s with ligand binding domains resembling those of at least 86 avian species have also been investigated (Farmahin et al 2013). AhR2s of birds have only been investigated in black-footed albatross (Phoebastria nigripes) and common cormorant (Phalacrocorax carbo) (Yasio et al 2007).</li> <li>American alligator (Alligator mississippiensis) is the only reptile for which AhR activation has been investigated (Oka et al 2016), AhR1A, AhR1B, and AhR2 of American alligator were assayed (Oka et al 2016).</li> <li>AhR1 of two amphibians have been investigated, namely African clawed frog (Xenopus laevis) and salamander (Ambystoma mexicanum) (Lavine et al 2005; Shoots et al 2015; Ohi et al 2003),</li> <li>AhR1s and AhR2s of several species of fish have been investigated, namely Atlantic salmon (Salmo salar), Atlantic tomcod (Microgadus tomcod), white sturgeon (Acipenser transmontanus), rainbow trout (Onchorhynchys mykiss), red seabream (Pagrus major), lake sturgeon (Acipenser fulvescens), and zebrafish (Danio rerio) (Andreasen et al 2002; Abnet et al 1999; Bak et al 2013; Doering et al 2014; 2015; Evans et al 2005; Hansson & Hahn 2008; Karchner et al 1999; Tanguay et al 1999; Wirgin et al 2011).</li> </ul> For demonstrative purposes, a luciferase reporter gene assay used to measure AHR1-mediated transactivation for avian species is described here. However, comparable assays are utilized for investigating AHR1s and AHR2s of all taxa. A monkey kidney cell line (Cos-7) that has low endogenous AHR1 expression was transfected with the appropriate avian AHR1 clone, cormorant ARNT1, a CYP1A5 firefly luciferase reporter construct and a Renilla luciferase vector to control for transfection efficiency. After seeding, the cells were exposed to DLC and luciferase activity was measured using a luminometer. Luminescence, which is proportional to the extent of AHR activation, is expressed as the ratio of firefly luciferase units to Renilla luciferase units <a href="#cite_note-Farmahin2012-13">[13]</a>. This particular assay was modified from its original version to increase throughput efficiency; (a) cells were seeded in 96-well plates rather than Petri dishes or 48- well plates, (b) DLCs were added directly to the wells without changing the cell culture medium, and (c) the same 96-well plates were used to measure luminescence without lysing the cells and transferring to another plate. Similar reporter gene assays have been used to measure AHR1 activation in domestic and wild species of birds, including the chicken, ring-necked pheasant (Phasianus colchicus), Japanese quail (Coturnix japonica), great cormorant, black-footed albatross and peregrine falcon (Falco peregrinus).<a href="#cite_note-Farmahin2013b-14">[14]</a><a href="#cite_note-Farmahin2012-13">[13]</a><a href="#cite_note-Fujisawa2012-15">[15]</a><a href="#cite_note-Lee2009-11">[11]</a><a href="#cite_note-Manning2012-16">[16]</a><a href="#cite_note-Mol2012-17">[17]</a> <h4>Transactivation in stable cell lines</h4> Stable cell lines have been developed and purified to the extent that each cell contains both the nuclear receptor and appropriate reporter vector, eliminating the variability associated with transfection <a href="#cite_note-Raucy2010-12">[12]</a>. A stable human cell line containing a luciferase reporter driven by multiple dioxin response elements has been developed that is useful in identifying AhR agonists and antagonists<a href="#cite_note-Yueh2005-18">[18]</a>. An added benefit of this model is the potential to multiplex 3 assays in a single well: receptor activation, cell viability and enzyme activity<a href="#cite_note-Raucy2010-12">[12]</a>. Such assays are used extensively in drug discovery due to their high throughput efficiency, and may serve just as useful for risk assessment purposes. <h3>Ligand-Binding Assays</h3> Ligand binding assays measure the ability of a test compound to compete with a labeled, high-affinity reference ligand for the LBD of a nuclear receptor. It is important to note that ligand binding does not necessitate receptor activation and therefore cannot distinguish between agonists and antagonists; however, binding affinities of AHR ligands are highly correlated with chemical potencies<a href="#cite_note-Poland1982-19">[19]</a> and can explain differences in species sensitivities to DLCs<a href="#cite_note-Hesterman2000-20">[20]</a><a href="#cite_note-Farmahin2014-21">[21]</a><a href="#cite_note-Karchner2006-22">[22]</a>; they are therefore worth mentioning. Binding affinity and efficacy have been used to develop structure-activity relationships for AHR disruption<a href="#cite_note-Hesterman2000-20">[20]</a><a href="#cite_note-Lee2015-23">[23]</a> that are potentially useful in risk-assessment. There has been tremendous progress in the development of ligand-binding assays for nuclear receptors that use homogenous assay formats (no wash steps) allowing for the detection of low-affinity ligands, many of which do not require a radiolabel and are amenable to high throughput screening<a href="#cite_note-Jones2003-24">[24]</a><a href="#cite_note-Raucy2010-12">[12]</a>. This author however was unable to find specific examples of such assays in the context of AHR binding and therefore some classic radioligand assays are described instead. <h4>Hydroxyapatite (HAP) binding assay</h4> The HAP binding assay makes use of an in vitro transcription/translation method to synthesize the AHR protein, which is then incubated with radiolabeled TDCPP and a HAP pellet. The occupied protein adsorbs to the HAP and the radioactivity is measured to determine saturation binding. An additional ligand can also be included in the mixture in order to determine its binding affinity relative to TCDD (competitive binding)<a href="#cite_note-Gasiewicz1982-25">[25]</a><a href="#cite_note-Karchner2006-22">[22]</a>. This assay is simple, repeatable and reproducible; however, it is insensitive to weak ligand-receptor interactions<a href="#cite_note-Karchner2006-22">[22]</a><a href="#cite_note-Farmahin2014-21">[21]</a><a href="#cite_note-Nakai1995-26">[26]</a>. <h4>Whole cell filtration binding assay</h4> Dold and Greenlee<a href="#cite_note-Dold1990-27">[27]</a> developed a method to detect specific binding of TCDD to whole mammalian cells in culture and was later modified by Farmahin et al.<a href="#cite_note-Farmahin2014-21">[21]</a> for avian species. The cultured cells are incubated with radiolabeled TCDD with or without the presence of a competing ligand and filtered. The occupied protein adsorbs onto the filter and the radioactivity is measured to determine saturation binging and/or competitive binding. This assay is able to detect weak ligand-receptor interactions that are below the detection limit of the HAP assay<a href="#cite_note-Farmahin2014-21">[21]</a>. <h3>Protein-DNA Interaction Assays</h3> The active AHR complexed with ARNT can be measured using protein-DNA interaction assays. Two methods are described in detail by Perez-Romero and Imperiale<a href="#cite_note-Perez2007-28">[28]</a>. Chromatin immunoprecipitation measures the interaction of proteins with specific genomic regions in vivo. It involves the treatment of cells with formaldehyde to crosslink neighboring protein-protein and protein-DNA molecules. Nuclear fractions are isolated, the genomic DNA is sheared, and nuclear lysates are used in immunoprecipitations with an antibody against the protein of interest. After reversal of the crosslinking, the associated DNA fragments are sequenced. Enrichment of specific DNA sequences represents regions on the genome that the protein of interest is associated with in vivo. Electrophoretic mobility shift assay (EMSA) provides a rapid method to study DNA-binding protein interactions in vitro. This relies on the fact that complexes of protein and DNA migrate through a nondenaturing polyacrylamide gel more slowly than free DNA fragments. The protein-DNA complex components are then identified with appropriate antibodies. The EMSA assay was found to be consistent with the LRG assay in chicken hepatoma cells dosed with dioxin-like compounds<a href="#cite_note-Heid2001-29">[29]</a>. <h3>In silico Approaches</h3> In silico homology modeling of the ligand binding domain of the AHR in combination with molecular docking simulations can provide valuable insight into the transactivation-potential of a diverse array of AHR ligands.  Such models have been developed for multiple AHR isoforms and ligands (high/low affinity, endogenous and synthetic, agonists and antagonists), and can accurately predict ligand potency based on their structure and physicochemical properties (Bonati et al 2017; Hirano et al 2015; Sovadinova et al 2006).

The AHR structure has been shown to contribute to differences in species sensitivity to DLCs in several animal models. In 1976, a 10-fold difference was reported between two strains of mice (non-responsive DBA/2 mouse, and responsive C57BL/6 14 mouse) in CYP1A induction, lethality and teratogenicity following TCDD exposure<a href="#cite_note-Poland1976-3">[3]</a>. This difference in dioxin sensitivity was later attributed to a single nucleotide polymorphism at position 375 (the equivalent position of amino acid residue 380 in chicken) in the AHR LBD<a href="#cite_note-Ema1994-30">[30]</a><a href="#cite_note-Poland1982-19">[19]</a><a href="#cite_note-Poland1994-31">[31]</a>. Several other studies reported the importance of this amino acid in birds and mammals<a href="#cite_note-Backlund2004-32">[32]</a><a href="#cite_note-Ema1994-30">[30]</a><a href="#cite_note-Karchner2006-22">[22]</a><a href="#cite_note-Murray2005-33">[33]</a><a href="#cite_note-Pandini2007-34">[34]</a><a href="#cite_note-Pandini2009-35">[35]</a><a href="#cite_note-Poland1994-31">[31]</a><a href="#cite_note-Ramadoss2004-36">[36]</a>. It has also been shown that the amino acid at position 319 (equivalent to 324 in chicken) plays an important role in ligand-binding affinity to the AHR and transactivation ability of the AHR, due to its involvement in LBD cavity volume and its steric effect<a href="#cite_note-Pandini2009-35">[35]</a>. Mutation at position 319 in the mouse eliminated AHR DNA binding<a href="#cite_note-Pandini2009-35">[35]</a>. The first study that attempted to elucidate the role of avian AHR1 domains and key amino acids within avian AHR1 in avian differential sensitivity was performed by Karchner et al.<a href="#cite_note-Karchner2006-22">[22]</a>. Using chimeric AHR1 constructs combining three AHR1 domains (DBD, LBD and TAD) from the chicken (highly sensitive to DLC toxicity) and common tern (resistant to DLC toxicity), Karchner and colleagues<a href="#cite_note-Karchner2006-22">[22]</a>, showed that amino acid differences within the LBD were responsible for differences in TCDD sensitivity between the chicken and common tern. More specifically, the amino acid residues found at positions 324 and 380 in the AHR1 LBD were associated with differences in TCDD binding affinity and transactivation between the chicken (Ile324_Ser380) and common tern (Val324_Ala380) receptors<a href="#cite_note-Karchner2006-22">[22]</a>. Since the Karchner et al. (2006) study was conducted, the predicted AHR1 LBD amino acid sequences were been obtained for over 85 species of birds and 6 amino acid residues differed among species<a href="#cite_note-Farmahin2013b-14">[14]</a><a href="#cite_note-Head2008-37">[37]</a> . However, only the amino acids at positions 324 and 380 in the AHR1 LBD were associated with differences in DLC toxicity in ovo and AHR1-mediated gene expression in vitro<a href="#cite_note-Farmahin2013b-14">[14]</a><a href="#cite_note-Head2008-37">[37]</a><a href="#cite_note-Manning2012-16">[16]</a>. These results indicate that avian species can be divided into one of three AHR1 types based on the amino acids found at positions 324 and 380 of the AHR1 LBD: type 1 (Ile324_Ser380), type 2 (Ile324_Ala380) and type 3 (Val324_Ala380)<a href="#cite_note-Farmahin2013b-14">[14]</a><a href="#cite_note-Head2008-37">[37]</a><a href="#cite_note-Manning2012-16">[16]</a>. <ul> <li>Little is known about differences in binding affinity of AhRs and how this relates to sensitivity in non-avian taxa.</li> <li>Low binding affinity for DLCs of AhR1s of African clawed frog (Xenopus laevis) and axolotl (Ambystoma mexicanum) has been suggested as a mechanism for tolerance of these amphibians to DLCs (Lavine et al 2005; Shoots et al 2015).</li> <li>Among reptiles, only AhRs of American alligator (Alligator mississippiensis) have been investigated and little is known about the sensitivity of American alligator or other reptiles to DLCs (Oka et al 2016).</li> <li>Among fishes, great differences in sensitivity to DLCs are known both for AhRs and for embryos among species that have been tested (Doering et al 2013; 2014).</li> <li>Differences in binding affinity of the AhR2 have been demonstrated to explain differences in sensitivity to DLCs between sensitive and tolerant populations of Atlantic Tomcod (Microgadus tomcod) (Wirgin et al 2011). <ul> <li>This was attributed to the rapid evolution of populations in highly contaminated areas of the Hudson River, resulting in a 6-base pair deletion in the AHR sequence (outside the LBD) and reduced ligand binding affinity, due to reduces AHR protein stability.</li> </ul> </li> <li>Information is not yet available regarding whether differences in binding affinity of AhRs of fishes are predictive of differences in sensitivity of embryos, juveniles, or adults (Doering et al 2013).</li> </ul> The AhR is a very conserved and ancient protein (95) and the AhR is present  in human and mice (96–98). The AhR is present in human physiology and pathology. The AhR is highly expressed at several important physiological barriers such as the placenta, lung, gastrointestinal system, and liver in human (Wakx, Marinelli, Watanabe).  In these tissues, the AhR is involved in both detoxication processes involving xenobiotic metabolizing enzymes such as cytochromes P450, and in immune functions translating chemical signals into immune defence pathways (Marinelli, Stobbe). Moreover, it has a regulatory role in human dendritic cells and myelination (Kado, Shackleford). The lung constitutes another barrier exposed to components of air pollution such as particles and hydrocarbons (air pollution, cigarette smoke). The AhR detects such hydrocarbons and protects the pulmonary cells from their deleterious effects through metabolization. The regulatory effect on blood cells of the AhR, balancing different related cell types, can be extended to the megakaryocytes and their precursors; indeed, StemRegenin 1 (SR1), an antagonist of the AhR increases the human population of CD34+CD41low cells, a fraction of very efficient precursors of proplatelets (Bock). The occurrence of a nystagmus has been subsequently diagnosed in humans bearing a AhR mutation (Borovok). In human cancer, the AhR has either a pro or con tumor effect depending on the tissue, the ligand, and the duration of the activation (Zudaire, Chang, Litzenburg, Gramatzki, Lin, Wang). In human breast cancer, the AhR is thoughts to be responsible of its progression (Goode, Kanno, Optiz, Novikov, Hall, Subramaniam, Barhoover). In human mammary benign cells, Brooks et al. noted that a high level of AhR was associated with a modified cell cycle (with a 50% increase in population doubling time in cells expressing the AhR by more than 3-fold) and EMT including increased cell migration. Narasimnhan et al. found that suppression of the AhR pathway had a pro-tumorigenic effect in vitro (EMT, tumor migration) in triple negative breast cancer. Many endogenous and exogenous ligands are present for the AhR in human (Optiz, Adachi, Schroeder, Rothhammer). Indoles, such as indole-3-carbinol or one of its secondary metabolites, 3-3'- Diindolylmethane, are degradation products found in cruciferous vegetables and characterized as AhR ligands (Ema, Kall, Miller) they are also inducers of the human and rat CYP1A1 (Optiz). FICZ is the most potent AhR ligand known to date: it has a stronger affinity than TCDD for the human AhR (TCDD Kd=0.48 nM/FICZ Kd=0.07 nM) (Coumoul).

High Unspecific

High

Embryo

High

Development

High

All life stages

High High High High High High High High High High High High High High High Not Specified

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Chem. 35 (1), 173-181.   Emmons, R.B.; Duncan, D.; Estes, P.A.; Kiefel, P.; Mosher, J.T.; Sonnenfeld, M.; Ward, M.P.; Duncan, I.; Crews, S.T. 1999. The spineless-aristapedia and tango bHLH-PAS proteins interact to control antennal and tarsal development in Drosophila. Development. 126, 3937-3945.   Evans, B.R.; Karchner, S.I.; Franks, D.G.; Hahn, M.E. 2005. Duplicate aryl hydrocarbon receptor repressor genes (ahrr1 and ahrr2) in the zebrafish Danio rerio: structure, function, evolution, and AHR-dependent regulation in vivo. Arch. Biochem. Biophys. 441, 151-167.   Hahn, M.E. 2002. Aryl hydrocarbon receptors: diversity and evolution. Chemico-Biol. Interact. 141, 131-160.   Hahn, M.E.; Karchner, S.I.; Evans, B.R.; Franks, D.G.; Merson, R.R.; Lapseritis, J.M. 2006. Unexpected diversity of aryl hydrocarbon receptors in non-mammalian vertebrates: Insights from comparative genomics. J. Exp. Zool. A. Comp. Exp. Biol. 305, 693-706.   Hahn, M.E.; Poland, A.; Glover, E.; Stegeman, J.J. 1994. Photoaffinity labeling of the Ah receptor: phylogenetic survey of diverse vertebrate and invertebrate species. Arch. Biochem. Biophys. 310, 218-228.   Hansson, M.C.; Hahn, M.E. 2008. Functional properties of the four Atlantic salmon (Salmo salar) aryl hydrocarbon receptor type 2 (AHR2) isoforms. Aquat. Toxicol. 86, 121-130.   Hansson, M.C.; Wittzell, H.; Persson, K.; von Schantz, T. 2004. Unprecedented genomic diversity of AhR1 and AhR2 genes in Atlantic salmon (Salmo salar L.). Aquat. Toxicol. 68 (3), 219-232.   Karchner, S.I.; Franks, D.G.; Hahn, M.E. (2005). AHR1B, a new functional aryl hydrocarbon receptor in zebrafish: tandem arrangement of ahr1b and ahr2 genes. Biochem. J. 392 (1), 153-161.   Karchner, S.I.; Powell, W.H.; Hahn, M.E. 1999. Identification and functional characterization of two highly divergent aryl hydrocarbon receptors (AHR1 and AHR2) in the Teleost Fundulus heteroclitus. Evidence for a novel subfamily of ligand-binding basic helix loop helix-Per-ARNT-Sim (bHLH-PAS) factors. J. Biol. Chem. 274, 33814-33824.   Lahvis, G.P.; Bradfield, C.A. 1998. Ahr null alleles: distinctive or different? Biochem. Pharmacol. 56, 781-787.   Lavine, J.A.; Rowatt, A.J.; Klimova, T.; Whitington, A.J.; Dengler, E.; Beck, C.; Powell, W.H. 2005. Aryl hydrocarbon receptors in the frog Xenopus laevis: two AhR1 paralogs exhibit low affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Toxicol. Sci. 88 (1), 60-72.   Oka, K.; Kohno, S.; Ohta, Y.; Guillette, L.J.; Iguchi, T.; Katsu, Y. (2016). Molecular cloning and characterization of the aryl hydrocarbon receptors and aryl hydrocarbon receptor nuclear translocators in the American alligator. Gen. Comp. Endo. 238, 13-22.   Pongratz, I.; Mason, G.G.; Poellinger, L. Dual roles of the 90-kDa heat shock protein hsp90 in modulating functional activities of the dioxin receptor. Evidence that the dioxin receptor functionally belongs to a subclass of nuclear receptors which require hsp90 both for ligand binding activity and repression of intrinsic DNA binding activity. J. Biol. Chem. 1992, 267 (19), 13728-13734   Prasch, A.L.; Teraoka, H.; Carney, S.A.; Dong, W.; Hiraga, T.; Stegeman, J.J.; Heideman, W.; Peterson, R.E. 2003. Toxicol. Sci. Aryl hydrocarbon receptor 2 mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish. 76 (1), 138-150.   Shoots, J.; Fraccalvieri, D.; Franks, D.G.; Denison, M.S.; Hahn, M.E.; Bonati, L.; Powell, W.H. 2015. An aryl hydrocarbon receptor from the salamander Ambystoma mexicanum exhibits low sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Enviro. Sci. Technol. 49, 6993-7001.   Tanguay, R.L.; Abnet, C.C.; Heideman, W. Peterson, R.E. (1999). Cloning and characterization of the zebrafish (Danio rerio) aryl hydrocarbon receptor1. Biochimica et Biophysica Act 1444, 35-48.   Van den Berg, M.; Birnbaum, L.; Bosveld, A.T.C.; Brunstrom, B.; Cook, P.; Feeley, M.; Giesy, J.P.; Hanberg, A.; Hasegawa, R.; Kennedy, S.W.; Kubiak, T.; Larsen, J.C.; van Leeuwen, R.X.R.; Liem, A.K.D.; Nolt, C.; Peterson, R.E.; Poellinger, L.; Safe, S.; Schrenk, D.; Tillitt, D.; Tysklind, M.; Younes, M.; Waern, F.; Zacharewski, T. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PECDFs for human and wildlife. Enviro. Hlth. Persp. 1998, 106, 775-792.   Van Tiem, L.A.; Di Giulio, R.T. 2011. AHR2 knockdown prevents PAH-mediated cardiac toxicity and XRE- and ARE-associated gene induction in zebrafish (Danio rerio). Toxicol. Appl. Pharmacol. 254 (3), 280-287.   Whitlock, J.P.; Okino, S.T.; Dong, L.Q.; Ko, H.S.P.; Clarke Katzenberg, R.; Qiang, M.; Li, W. 1996. Induction of cytochrome P4501A1: a model for analyzing mammalian gene transcription. Faseb. J. 10, 809-818.   Wirgin, I.; Roy, N.K.; Loftus, M.; Chambers, R.C.; Franks, D.G.; Hahn, M.E. 2011. Mechanistic basis of resistance to PCBs in Atlantic tomcod from the Hudson River. Science. 331, 1322-1324.   Yamauchi, M.; Kim, E.Y.; Iwata, H.; Shima, Y.; Tanabe, S. Toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing red seabream (Pagrus major) embryos: an association of morphological deformities with AHR1, AHR2 and CYP1A expressions. Aquat. Toxicol. 2006, 16, 166-179.   Yasui, T.; Kim, E.Y.; Iawata, H.; Franks, D.G.; Karchner, S.I.; Hahn, M.E.; Tanabe, S. 2007. Functional characterization and evolutionary history of two aryl hydrocarbon receptor isoforms (AhR1 and AhR2) from avian species. Toxicol. Sci. 99 (1), 101-117. <div>Hirano, M.; Hwang, JH; Park, HJ; Bak, SM; Iwata, H. and Kim, EY (2015) In Silico Analysis of the Interaction of Avian Aryl Hydrocarbon Receptors and Dioxins to Decipher Isoform-, Ligand-, and Species-Specific Activations.<cite> Environmental Science & Technology</cite> 49 (6): 3795-3804.DOI: 10.1021/es505733f</div> <div> </div> Bonati, L.; Corrada, D.; Tagliabue, S.G.; Motta, S. (2017) Molecular modeling of the AhR structure and interactions can shed light on ligand-dependent activation and transformation mechanisms. Current Opinion in Toxicology 2: 42-49. https://doi.org/10.1016/j.cotox.2017.01.011. Sovadinová, I. , Bláha, L. , Jano&scaron;ek, J. , Hilscherová, K. , Giesy, J. P., Jones, P. D. and Holoubek, I. (2006), Cytotoxicity and aryl hydrocarbon receptor‐mediated activity of N‐heterocyclic polycyclic aromatic hydrocarbons: Structure‐activity relationships. Environmental Toxicology and Chemistry, 25: 1291-1297. doi:<a href="https://doi.org/10.1897/05-388R.1">10.1897/05-388R.1</a>     Wakx A, Nedder M, Tomkiewicz-Raulet C, Dalmasso J, Chissey A, et al. 2018. Expression, Localization, and Activity of the Aryl Hydrocarbon Receptor in the Human Placenta. Int J Mol Sci. 19(12)   Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, et al. 1994. Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.   Kall MA, Vang O, Clausen J. 1996. Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis. 17(4):793–99   Miller CA. 1997. Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds. J. Biol. Chem. 272(52):32824–29   Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, et al. 2011. An endogenous tumour promoting ligand of the human aryl hydrocarbon receptor. Nature. 478(7368):197–203   Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, et al. 2001. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J. Biol. Chem. 276(34):31475–78   Marinelli L, Martin-Gallausiaux C, Bourhis J-M, B.guet-Crespel F, Blotti.re HM, Lapaque N. 2019. Identification of the novel role of butyrate as AhR ligand in human intestinal epithelial cells. Sci Rep. 9(1):643   Stobbe-Maicherski N, Wolff S, Wolff C, Abel J, Sydlik U, et al. 2013. The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells. FEBS J. 280(24):6681–90   Kado S, Chang WLW, Chi AN, Wolny M, Shepherd DM, Vogel CFA. 2017. Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells. Arch Toxicol. 91(5):2209–21   Bock KW. 2019. Human AHR functions in vascular tissue: Pro- and anti-inflammatory responses of AHR agonists in atherosclerosis. Biochem Pharmacol. 159:116–20   Schroeder JC, Dinatale BC, Murray IA, Flaveny CA, Liu Q, et al. 2010. The uremic toxin 3- indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry. 49(2):393–400   Watanabe I, Tatebe J, Namba S, Koizumi M, Yamazaki J, Morita T. 2013. Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. Circ J. 77(1):224–30   Shackleford G, Sampathkumar NK, Hichor M, Weill L, Meffre D, et al. 2018. Involvement of Aryl hydrocarbon receptor in myelination and in human nerve sheath tumorigenesis. Proc Natl Acad Sci U S 115(6):E1319–28     Zudaire E, Cuesta N, Murty V, Woodson K, Adams L, et al. 2008. The aryl hydrocarbon receptor repressor is a putative tumor suppressor gene in multiple human cancers. J Clin Invest. 118(2):640–50   Goode GD, Ballard BR, Manning HC, Freeman ML, Kang Y, Eltom SE. 2013. Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB- 231 human breast cancer cell line. Int J Cancer. 133(12):2769–80   Chang JT, Chang H, Chen P-H, Lin S-L, Lin P. 2007. Requirement of aryl hydrocarbon receptor overexpression for CYP1B1 up-regulation and cell growth in human lung adenocarcinomas. Clin Cancer Res. 13(1):38–45   Kanno Y, Takane Y, Izawa T, Nakahama T, Inouye Y. 2006. The inhibitory effect of aryl hydrocarbon receptor repressor (AhRR) on the growth of human breast cancer MCF-7 cells. Biol Pharm Bull. 29(6):1254–57   Goode G, Pratap S, Eltom SE. 2014. Depletion of the aryl hydrocarbon receptor in MDA-MB- 231 human breast cancer cells altered the expression of genes in key regulatory pathways of cancer. PLoS One. 9(6):e100103   Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, et al. 2011. An endogenous tumour promoting ligand of the human aryl hydrocarbon receptor. Nature. 478(7368):197–203   Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A, et al. 2016. An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells. Mol Pharmacol. 90(5):674–88   Litzenburger UM, Opitz CA, Sahm F, Rauschenbach KJ, Trump S, et al. 2014. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget. 5(4):1038–51   Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS. 2010. Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. Mol Endocrinol. 24(2):359–69   Gramatzki D, Pantazis G, Schittenhelm J, Tabatabai G, K.hle C, et al. 2009. Aryl hydrocarbon receptor inhibition downregulates the TGF-beta/Smad pathway in human glioblastoma cells. Oncogene. 28(28):2593–2605   Subramaniam V, Ace O, Prud’homme GJ, Jothy S. 2011. Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells. Exp Mol Pathol. 90(1):116–22   Rothhammer V, Borucki DM, Kenison JE, Hewson P, Wang Z, et al. 2018. Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep. 8(1):4970   Lin P, Chang H, Tsai W-T, Wu M-H, Liao Y-S, et al. 2003. Overexpression of aryl hydrocarbon receptor in human lung carcinomas. Toxicol Pathol. 31(1):22–30   Barhoover MA, Hall JM, Greenlee WF, Thomas RS. 2010. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol Pharmacol. 77(2):195–201   Wang K, Li Y, Jiang Y-Z, Dai C-F, Patankar MS, et al. 2013. An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells. Cancer Lett. 340(1):63–71   Borovok N, Weiss C, Sharkia R, Reichenstein M, Wissinger B, et al. 2020. Gene and Protein Expression in Subjects With a Nystagmus-Associated AHR Mutation. Front Genet. 11:582796 Harper PA, Riddick DS, Okey AB. Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol. 2006;72(3):267-79. Wright EJ, De Castro KP, Joshi AD, Elferink CJ. Canonical and non-canonical aryl hydrocarbon receptor signaling pathways. Curr Opin Toxicol. 2017;2:87-92. Hernández-Ochoa I, Karman BN, Flaws JA. The role of the aryl hydrocarbon receptor in the female reproductive system. Biochem Pharmacol. 2009;77(4):547-59.     AOPWiki 2016-11-29T18:41:22

2025-05-31T07:56:20

Over-expression of PD-L1 in cancer cells

Molecular

PD-L1 (Programmed Death-Ligand 1, or B7-H1/CD274) is known to be a promising therapeutic target in the development of anti-tumor treatments. This ligand can be expressed in several forms: cytoplasmic, membrane-bound, soluble, or in extracellular vesicles. Based on current knowledge, the membrane form is the most well-documented, particularly for inhibiting T cell activity (Lin et al., 2024). Its physiological role is to bind to PD1 (or CD279), its receptor on immune cells, giving it an essential immunosuppressive role (Butte et al., 2007). This is why this ligand is well studied for treatment related to immunosuppressive disease (Tomlins et al., 2023). PD-L1 is a membrane protein belonging to the immunoglobulin family (IgSF). It has two main domains: an N-terminal variable immunoglobulin (IgV) domain and a C-terminal constant immunoglobulin (IgC) domain (Lin et al., 2008) (Jiang et al., 2019). It is the IgV domain that allows interaction with the PD-1 receptor, which is mainly expressed on T lymphocytes but also present in slightly lower levels on B lymphocytes. In the context of cancer, tumor cells overexpress this ligand, which contributes to immune escape and the establishment of the Tumor MicroEnvironment (TME) (Riella et al., 2012).

CL:0000235

CL macrophage

Butte, M.J., Keir, M.E., Phamduy, T.B., Sharpe, A.H., Freeman, G.J., 2007. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122. https://doi.org/10.1016/j.immuni.2007.05.016 Jiang, Y., Chen, M., Nie, H., Yuan, Y., 2019. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum. Vaccines Immunother. 15, 1111–1122. https://doi.org/10.1080/21645515.2019.1571892 Lin, D.Y., Tanaka, Y., Iwasaki, M., Gittis, A.G., Su, H.-P., Mikami, B., Okazaki, T., Honjo, T., Minato, N., Garboczi, D.N., 2008. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl. Acad. Sci. U. S. A. 105, 3011–3016. https://doi.org/10.1073/pnas.0712278105 Lin, X., Kang, K., Chen, P., Zeng, Z., Li, G., Xiong, W., Yi, M., Xiang, B., 2024. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol. Cancer 23, 108. https://doi.org/10.1186/s12943-024-02023-w Riella, L.V., Paterson, A.M., Sharpe, A.H., Chandraker, A., 2012. Role of the PD-1 Pathway in the Immune Response. Am. J. Transplant. Off. J. Am. Soc. Transplant. Am. Soc. Transpl. Surg. 12, 2575–2587. https://doi.org/10.1111/j.1600-6143.2012.04224.x Tomlins, S.A., Khazanov, N.A., Bulen, B.J., Hovelson, D.H., Shreve, M.J., Lamb, L.E., Matrana, M.R., Burkard, M.E., Yang, E.S.-H., Edenfield, W.J., Dees, E.C., Onitilo, A.A., Thompson, M., Buchschacher, G.L., Miller, A.M., Menter, A., Parsons, B., Wassenaar, T., Hwang, L.C., Suga, J.M., Siegel, R., Irvin, W., Nair, S., Slim, J.N., Misleh, J., Khatri, J., Masters, G., Thomas, S., Safa, M., Anderson, D.M., Kwiatkowski, K., Mitchell, K., Hu-Seliger, T., Drewery, S., Fischer, A., Plouffe, K., Czuprenski, E., Hipp, J., Reeder, T., Vakil, H., Johnson, D.B., Rhodes, D.R., 2023. Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit. Commun. Med. 3, 14. https://doi.org/10.1038/s43856-023-00243-7   AOPWiki 2025-05-15T12:40:51

2025-09-30T12:12:18

Increased of Treg/Th17 cell ratio

Dysregulation of Treg/Th17 cell ratio

Cellular

<div> The ratio between Th17 and T regulatory (Treg) cells is essential for maintaining a balanced immune environment (Noack and Miossec, 2014; Fasching et al., 2017; Lee, 2018). Both cells are derived from CD4+ lymphocytes, a subset of T lymphocytes. On one hand, the role of Treg is to dampen the immune response by tempering the activity of CTLs, also called CD8+ cytotoxic T cells. Tregs are induced by TGF-β and FoxP3 (Forkhead box P3), which plays a major role in the activation from the naïve state to the activated Treg state. Consequently, the expression of FoxP3 well reflects the Treg activity (Fontenot et al., 2003); they are also characterized by a high expression of CD25 (Interleukin 2 receptor ɑ-chain). To highlight their immunosuppressive role in the TME, their elimination has been shown to lead to tumor immunity (Shimizu et al., 1999). On the other hand, the role of Th17 cells is to enhance the immune response by producing pro-inflammatory signals like IL-17, IL-22, or IL-23. Naive T cells are also activated partly by TGF-β, but a co-stimulation with IL-6 or IL-21 is necessary; indeed, the absence of these proinflammatory cytokines leads to Treg differentiation instead (Bettelli et al., 2006). In short, both Th17 and Treg require TGF-β to be activated; however, in a stressed environment, the production of IL-6 by other immune cells leads to a preferential differentiation towards the Th17 phenotype. In cancer or in autoimmune diseases, this balance between the two phenotypes is disturbed  with a higher presence of Treg and leads to adverse outcomes such as tumor maintenance (Lin et al., 2019; He et al., 2020; Yan et al., 2020). </div>

Bettelli, E., Carrier, Y., Gao, W. et al. (2006). Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238. https://doi.org/10.1038/nature04753. Fasching, P., Stradner, M., Graninger, W. et al. (2017). Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules 22, 134. https://doi.org/10.3390/molecules22010134. Fontenot, J. D., Gavin, M. A. and Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4, 330–336. https://doi.org/10.1038/ni904. He, X., Liang, B. and Gu, N. (2020). Th17/Treg Imbalance and Atherosclerosis. Dis Markers 2020, 8821029. https://doi.org/10.1155/2020/8821029. Lee, G. R. (2018). The Balance of Th17 versus Treg Cells in Autoimmunity. Int J Mol Sci 19, 730. https://doi.org/10.3390/ijms19030730. Lin, W., Niu, Z., Zhang, H. et al. (2019). Imbalance of Th1/Th2 and Th17/Treg during the development of uterine cervical cancer. Int J Clin Exp Pathol 12, 3604–3612 Noack, M. and Miossec, P. (2014). Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13, 668–677. https://doi.org/10.1016/j.autrev.2013.12.004. Shimizu, J., Yamazaki, S. and Sakaguchi, S. (1999). Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163, 5211–5218 Yan, J.-B., Luo, M.-M., Chen, Z.-Y. et al. (2020). The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. J Immunol Res 2020, 8813558. https://doi.org/10.1155/2020/8813558. AOPWiki 2025-05-16T04:45:51

2026-02-24T11:48:42

CTL cytotoxic activity disruption

CTL cytotoxicity

Cellular

<div> CTLs or CD8+ T cells are key components of the adaptive immune system, playing a crucial role in protecting against viral infections, bacteria, and tumor development. In the context of cancer, CTLs kill tumor cells after recognizing tumor-derived peptides presented on MHC class I molecules through their T-cell receptor. Upon activation, CTLs form an immunological synapse with the target cell (including cancer cells) and deploy three main killing pathways(Raskov et al., 2021): first, these cells can kill target cells indirectly through the release of cytokine factors like TNFα or IFN-γ (Hoekstra et al., 2024). Second, in the granule exocytosis pathway, CTLs release perforin, which forms pores in the tumor cell membrane, allowing granzymes to enter and trigger caspase-dependent apoptosis. Finally, in the death receptor pathway, CTLs express Fas ligand (FasL) that binds Fas (CD95) on the cell surface of tumor cells, activating their extrinsic apoptotic cascade (Preglej and Ellmeier, 2022). However, the cancer cells can deactivate and inhibit CTLs, and, as a result, facilitate the tumor immune evasion. In this context, the effectiveness of CTLs is hindered by immunosuppressive mechanisms involving cancer-associated fibroblasts, M2 macrophages, and particularly regulatory T cells (Tregs), which can block the CTLs cytotoxic activity through the TGF-β pathway (Chen et al., 2005). Alternatively, continuous antigenic stimulation also leads to CTLs exhaustion, generating heterogeneous subpopulations, some of which remain responsive to immune checkpoint blockade (Chen et al., 2024). Anti-cancer therapies targeting PD1/PD-L1 aim to restore CTLs function. Combined approaches, such as inhibiting the ICoS (Inducible Co-Stimulator) pathway before a PD1 therapy, are promising (Geels et al., 2024). Finally, the adoption of genetically engineered CTLs (CAR-T) is an example of advances in enhancing their specificity and tumor-killing efficacy (Brudno et al., 2024). </div>

Brudno, J. N., Maus, M. V. and Hinrichs, C. S. (2024). CAR T Cells and T-Cell Therapies for Cancer. JAMA 332, 1924–1935. https://doi.org/10.1001/jama.2024.19462. Chen, M.-L., Pittet, M. J., Gorelik, L. et al. (2005). Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proceedings of the National Academy of Sciences 102, 419–424. https://doi.org/10.1073/pnas.0408197102. Chen, Y., Yu, D., Qian, H. et al. (2024). CD8+ T cell-based cancer immunotherapy. J Transl Med 22, 394. https://doi.org/10.1186/s12967-024-05134-6. Geels, S. N., Moshensky, A., Sousa, R. S. et al. (2024). Interruption of the Intratumor CD8+ T cell:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy. Cancer Cell 42, 1051-1066.e7. https://doi.org/10.1016/j.ccell.2024.05.013. Hoekstra, M. E., Slagter, M., Urbanus, J. et al. (2024). Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment. Cancer Cell 42, 157-167.e9. https://doi.org/10.1016/j.ccell.2023.12.010. Preglej, T. and Ellmeier, W. (2022). CD4+ Cytotoxic T cells – Phenotype, Function and Transcriptional Networks Controlling Their Differentiation Pathways. Immunology Letters 247, 27–42. https://doi.org/10.1016/j.imlet.2022.05.001. Raskov, H., Orhan, A., Christensen, J. P. et al. (2021). Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer 124, 359–367. https://doi.org/10.1038/s41416-020-01048-4.   AOPWiki 2025-05-22T12:01:17

2026-02-24T11:49:25

Increased, tumor growth

tumor growth

Organ

Tumor growth refers to the increase in size of a cancer due to the uncontrolled proliferation of cells. The mechanisms have been detailed in Hanahan et al. hallmarks of cancer: <ul> <li style="text-align:justify">Initiation: Tumor growth often begins with the initiation of genetic alterations in normal cells. This can result from mutations caused by various factors such as exposure to carcinogens, genetic predisposition, or viral infections.</li> <li style="text-align:justify">Uncontrolled Cell Proliferation: One of the hallmark features of tumor growth is uncontrolled cell division. Initiating mutations in key regulatory genes, such as oncogenes and tumor suppressor genes, disrupt normal cell cycle control, leading to continuous and unregulated cell proliferation. The PI3K/AKT/mTOR pathway regulates cell growth, proliferation, and survival. Mutations in genes like PTEN, a negative regulator of this pathway, can lead to its hyperactivation, promoting tumor growth (Janaku, Paplomatta). The MAPK is involved in cell proliferation, differentiation, and survival. Mutations in genes like BRAF and KRAS can activate this pathway, contributing to uncontrolled cell growth and tumor development (Steelman, Guo).</li> <li style="text-align:justify">Angiogenesis: Tumors require a blood supply for sustained growth. Angiogenesis, the formation of new blood vessels, is induced by the tumor to ensure a nutrient and oxygen supply. Tumor cells release pro-angiogenic factors, promoting the development of a network of blood vessels within and around the tumor (Nishida).</li> <li style="text-align:justify">Metabolic Adaptations: Tumor cells often exhibit altered metabolism, characterized by increased glycolysis even in the presence of oxygen (Warburg effect). This metabolic shift supports the high energy demands of rapidly dividing cells (Pham). </li> <li style="text-align:justify">Tumor Microenvironment: Tumor growth involves interactions with the surrounding microenvironment, including stromal cells, immune cells, and the extracellular matrix. Tumor cells can influence their microenvironment to promote their survival and expansion. Fibroblasts transform into cancer associated fibroblasts to support tumor growth by producing growth factors and promoting angiogenesis (Asif).</li> <li style="text-align:justify">Immune Evasion: Malignant tumors can develop mechanisms to evade the immune system. This may involve downregulation of antigens, inhibitory signals to immune cells, or the recruitment of immunosuppressive cells, allowing the tumor to escape immune detection and attack (Hiam).</li> <li style="text-align:justify">Invasion and Metastasis: Malignant tumors can invade nearby tissues and, in advanced stages, metastasize to distant organs. Invasion involves the penetration of tumor cells into surrounding tissues, while metastasis is the spread of cancer cells to other parts of the body via the bloodstream or lymphatic system.</li> <li style="text-align:justify">Tumor Dormancy: In some cases, tumor growth may enter a state of dormancy, where the proliferation of cancer cells is temporarily halted. Dormant tumors can later resume growth, posing challenges in terms of early detection and treatment (Endo).</li> </ul>     Detailed here are key molecular mechanisms associated with breast tumor growth (Hanahan): <ul> <li style="text-align:justify">Genetic Mutations: Genetic alterations in key oncogenes (e.g., HER2, MYC, PIK3CA) promote cell proliferation whereas mutations in tumor suppressor genes (e.g., TP53, BRCA1, BRCA2) remove inhibitory controls on cell growth. (Knudson)</li> <li style="text-align:justify">Hormone Receptor Signaling: ER-positive breast cancers (70% of cancers) respond to estrogen stimulation, promoting cell proliferation. Endocrine therapies targeting ER signaling are effective in treating these cancers (Elikatkin).</li> <li style="text-align:justify">HER2/Neu overexpression : Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) promotes cell growth and survival (Slamon, Elikatkin).</li> <li style="text-align:justify">PI3K/AKT/mTOR Pathway Activation: Mutations in the PIK3CA gene or activation of PI3K signaling pathway promotes cell survival and proliferation. Phosphoinositide 3-kinase (PI3K) activation leads to downstream signaling through AKT and mTOR, promoting cell growth and protein synthesis (Janku, Paplomata)</li> <li>MAPK pathway: This pathway is involved in cell proliferation, differentiation, and survival. Mutations in this pathway can also contribute to breast cancer development (Steelman).</li> <li style="text-align:justify">Cell Cycle Regulation: Dysregulation of cyclin-dependent kinase (CDK) and cyclin complexes controls the cell cycle progression. Inactivation of the p16 tumor suppressor and retinoblastoma protein (pRB) pathway contributes to uncontrolled cell cycle progression (Witkiewicz).</li> <li style="text-align:justify">Apoptosis Evasion: Overexpression of anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) inhibits programmed cell death. Mutations or inactivation of pro-apoptotic proteins (e.g., p53) hinders apoptotic responses.</li> <li style="text-align:justify">Angiogenesis Stimulation: Vascular endothelial growth factor (VEGF) and its receptors stimulate angiogenesis, ensuring a blood supply for tumor growth. Hypoxia-inducible factor 1-alpha (HIF-1α) activates angiogenic responses in low-oxygen conditions.</li> <li style="text-align:justify">Epithelial-Mesenchymal Transition (EMT): Downregulation of adhesion molecules (e.g., E-cadherin) leads to increased cell mobility. Acquisition of mesenchymal characteristics enhances the ability of tumor cells to invade surrounding tissues (Drasin).</li> <li style="text-align:justify">Extracellular Matrix (ECM) Remodeling: Overexpression of MMPs facilitates ECM degradation, enabling tumor invasion.</li> <li style="text-align:justify">Metastasis Formation: Tumor cells invade surrounding tissues and enter blood or lymphatic vessels. Ability of tumor cells to survive in the bloodstream. Tumor cells exit circulation, invade distant tissues, and establish secondary tumors.</li> </ul>

Many different assays can be used to measure tumor growth directly: <ul> <li style="text-align:justify">Clinical measurement and palpation</li> <li style="text-align:justify">Histopathology with fluorescence imaging, dyes or weight</li> <li style="text-align:justify">Serum Biomarkers</li> <li style="text-align:justify">Imagery using caliper measurement on Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), or ultrasound can provide detailed images for volume calculation.</li> <li style="text-align:justify">Positron Emission Tomography (PET) Imaging : measurement of metabolic activity using radioactive tracers.</li> <li style="text-align:justify">In vivo models: xenograft tumor models, orthotopic models, genetically engineered mouse models</li> </ul>     Indirect assays can also be used: <ul> <li style="text-align:justify">Bioluminescence Imaging (BLI): Measurement of light emitted by luciferase-expressing tumor cells.</li> <li style="text-align:justify">Flow Cytometry: Quantification of tumor cells based on DNA content.</li> <li style="text-align:justify">Cell Proliferation Assays (MTT/MTS, BrdU)</li> <li style="text-align:justify">Colony formation</li> </ul>

Human, mice

High Mixed

High

Adults

High

Asif PJ, Longobardi C, Hahne M, Medema JP. The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis. Cancers (Basel). 2021 Sep 21;13(18):4720. doi: 10.3390/cancers13184720. PMID: 34572947; PMCID: PMC8472587.   Witkiewicz AK, Knudsen ES. Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. 2014 May 7;16(3):207. doi: 10.1186/bcr3652. PMID: 25223380; PMCID: PMC4076637.   Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way. J Breast Health. 2015 Apr 1;11(2):59-66. doi: 10.5152/tjbh.2015.1669. PMID: 28331693; PMCID: PMC5351488.   Phan LM, Yeung SC, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014 Mar;11(1):1-19. doi: 10.7497/j.issn.2095-3941.2014.01.001. PMID: 24738035; PMCID: PMC3969803.   Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag. 2006;2(3):213-9. doi: 10.2147/vhrm.2006.2.3.213. PMID: 17326328; PMCID: PMC1993983.   Drasin, D.J., Robin, T.P. & Ford, H.L. Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res 13, 226 (2011). https://doi.org/10.1186/bcr3037   Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014 Jul;6(4):154-66. doi: 10.1177/1758834014530023. PMID: 25057302; PMCID: PMC4107712.   Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y and Hu LL: ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med 19: 1997-2007, 2020   Hiam-Galvez, K.J., Allen, B.M. & Spitzer, M.H. Systemic immunity in cancer. Nat Rev Cancer 21, 345–359 (2021). <a href="https://doi.org/10.1038/s41568-021-00347-z" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/s41568-021-00347-z</a>   Endo H, Inoue M. Dormancy in cancer. Cancer Sci. 2019 Feb;110(2):474-480. doi: 10.1111/cas.13917. Epub 2019 Jan 11. PMID: 30575231; PMCID: PMC6361606.   Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J., Wong, S. G., Keith, D. E., ... & McGuire, W. L. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (New York, N.Y.), 248(4960), 787-792. <a href="https://pubmed.ncbi.nlm.nih.gov/2470152/" style="color:#467886; text-decoration:underline">https://pubmed.ncbi.nlm.nih.gov/2470152/</a>   Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57-70. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446472/" style="color:#467886; text-decoration:underline">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446472/</a>   Knudson, A. G. (2000). Two-hit hypothesis for inherited breast cancer: an update. Carcinogenesis, 21(3), 439-448. <a href="https://pubmed.ncbi.nlm.nih.gov/9212799/" style="color:#467886; text-decoration:underline">https://pubmed.ncbi.nlm.nih.gov/9212799/</a>   Janku, F., Yap, T. A., & Westin, J. (2018). Targeting the PI3K pathway in human cancer: rationale and emerging clinical landscapes. Journal of Clinical Oncology, 36(15), 1550-1562. <a href="https://pubmed.ncbi.nlm.nih.gov/29508857/" style="color:#467886; text-decoration:underline">https://pubmed.ncbi.nlm.nih.gov/29508857/</a>   Steelman, L. S., Chappell, W. P., deCarvalho, T. B., Lowe, S., & Davies, M. (2004. Ras/Raf/MEK/ AOPWiki 2022-02-15T15:16:25

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An increase in AHR activity in both immune cells and tumor cells is linked with a higher expression of PD-L1 (Fang et al., 2021; Jiang et al., 2024). Numerous studies have shown that the activation of AHR by its ligands, such as TCDD or kynurenine, can be linked to an overexpression of PD1 (Liu et al., 2018; Helou et al., 2023) and PD-L1 in cancer cells (Kenison et al., 2021; Han et al., 2023; Snyder et al., 2025). Also, Han et al. (2023) demonstrated by chromatin immunoprecipitation (ChIP) that AHR binds to the PD-L1 promoter and controls its transcription in non-small cell lung cancer (NSCLC) (Han et al., 2023). A study also observed a self-activation loop of the AHR signaling pathway through IDO1 and kynurenine; thus, IDO1 is also a key element in the activation of AHR and, consequently, the overexpression of PD-L1 in cancer cells (Snyder et al., 2025). Amobi-McCloud et al. (2021) demonstrated an increase in IDO1 expression in tumor-infiltrating CTLs, macrophages, and non-cancer cells from mouse ovarian cancer. With results showing an increase in the PD1+ cells measured by cell cytometry in T lymphocytes, the authors conclude an activation of the PD1/PD-L1 axis mediated by the AHR pathway through the increase of IDO1 expression (Amobi-McCloud et al., 2021).

Amobi-McCloud, A., Muthuswamy, R., Battaglia, S. et al. (2021). IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation. Front Immunol 12, 678999. https://doi.org/10.3389/fimmu.2021.678999. Fang, W., Zhou, T., Shi, H. et al. (2021). Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion. J Exp Clin Cancer Res 40, 4. https://doi.org/10.1186/s13046-020-01786-6. Han, S.-C., Wang, G.-Z., Yang, Y.-N. et al. (2023). Nuclear AhR and membranous PD-L1 in predicting response of non-small cell lung cancer to PD-1 blockade. Signal Transduct Target Ther 8, 191. https://doi.org/10.1038/s41392-023-01416-5. Helou, D. G., Quach, C., Fung, M. et al. (2023). Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells. J Allergy Clin Immunol 151, 526-538.e8. https://doi.org/10.1016/j.jaci.2022.07.022. Jiang, X., Wang, J., Lin, L. et al. (2024). Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity. Signal Transduct Target Ther 9, 352. https://doi.org/10.1038/s41392-024-02042-5. Kenison, J. E., Wang, Z., Yang, K. et al. (2021). The aryl hydrocarbon receptor suppresses immunity to oral squamous cell carcinoma through immune checkpoint regulation. Proc Natl Acad Sci U S A 118, e2012692118. https://doi.org/10.1073/pnas.2012692118. Liu, Y., Liang, X., Dong, W. et al. (2018). Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell 33, 480-494.e7. https://doi.org/10.1016/j.ccell.2018.02.005. Snyder, M., Wang, Z., Lara, B. et al. (2025). The aryl hydrocarbon receptor controls IFN-γ-induced immune checkpoints PD-L1 and IDO via the JAK/STAT pathway in lung adenocarcinoma. J Immunol, vkae023. https://doi.org/10.1093/jimmun/vkae023. AOPWiki 2025-05-16T04:14:07

2026-02-25T04:37:50

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<div> Considering the increased expression of PD-L1 in cancer cells, in the tumor microenvironment, numerous studies have reported increased expression of its receptor, PD1, in T lymphocytes (Chemnitz et al., 2004; Dorfman et al., 2006; Simon and Labarriere, 2017). PD-L1 influences Treg and Th17 differentiation through binding to PD1: it downregulates Akt, mTOR, and ERK2 during Treg differentiation (Francisco et al., 2009) while activating STAT1 and inhibiting STAT3 in Th17 cells (Zhang et al., 2017). Consequently, a higher expression of PD-L1, particularly in cancer cells, leads to a decrease in both the number and activity of Th17 cells, as well as an increased activity of Treg cells (Francisco et al., 2009; Ohaegbulam et al., 2015), which are known to suppress the immune response and promote tolerance. Other studies have used inhibitory mechanisms to examine Treg function, and to date, two main therapeutic strategies are based on these pathways: CTLA-4 and PD1/PD-L1 blockade. The CTLA-4 pathway acts in the early stages of immune activation to limit T cell proliferation, unlike the PD1/PD-L1 pathway, modulating later the lymphocytes that are already involved in the response. Simpson et al. in 2013 used CTLA-4 KO mice and showed a depletion of Treg in the TME (Simpson et al., 2013); in another study, patients received an anti-CTLA-4, an anti-PD-L1, or both therapies. The authors found that the anti-CTLA-4 therapy improves Th17 expansion. On the other hand, Li et al. (2022) presented several PD1 inhibitors (such as Nivolumab, Pembrolizumab, and Camrelizumab), as well as monoclonal antibodies against PD-L1 (such as Atezolizumab and Durvalumab) (Li et al., 2022): these drugs reduce the activation of the PD1/PD-L1 axis, thereby reducing the population of Treg cells; this restores a more balanced ratio between Tregs and Th17 cells, which consequently enhances tumor immunosensitivity. </div>

Moderate Unspecific

AOPWiki 2025-05-16T04:46:11

2026-02-25T08:45:02

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AOPWiki 2025-05-22T12:01:44

2025-05-22T12:01:44

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AOPWiki 2025-06-10T09:59:55

2025-06-10T09:59:55

AhR activation leading to cancer progression via immunosuppression

AhR activation leading to cancer progression

Léo SPORTES-MILOT

Etienne BLANC Xavier COUMOUL Annamaria Colacci Julija Filipovska

BY-SA

2.7

Due to the evolution of our society, numerous chemical compounds are created, produced, and released into the environment. However, the impact on the environment and human health remains to be demonstrated for many of them. The AhR receptor is known to be an essential receptor in the metabolism of these xenobiotics. Moreover, AhR regulates many cellular signaling pathways, notably in immunity. Thus, the over-activation of AhR could lead to harmful effects. This AOP focuses on the mechanisms linking AhR activation (MIE) and immunosuppression that can lead to tumor progression (AO).   A literature analysis using artificial intelligences such as AOP-helpfinder or Perplexity highlighted 55 articles. After analyzing these articles, clear links between AhR activation, PD-L1 (Program Death Ligand) expression, the impact on lymphocytes, and finally cancer progression were identified as KEs and KER.   These analyses bring together scientific results in vitro and in vivo, several types of cancers in humans and animals, as well as reviews and articles.

The AHR can be activated by several structurally diverse chemicals, but binds preferentially to planar halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons. Dioxin-like compounds (DLCs), which include polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and certain polychlorinated biphenyls (PCBs), are among the most potent AHR ligands<a href="#cite_note-Denison2011-38">[38]</a>. Only a subset of PCDD, PCDF and PCB congeners has been shown to bind to the AHR and cause toxic effects to those elicited by TCDD. Until recently, TCDD was considered to be the most potent DLC in birds<a href="#cite_note-Van1998-39">[39]</a>; however, recent reports indicate that 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) is more potent than TCDD in some species of birds.<a href="#cite_note-Cohen2011b-40">[40]</a><a href="#cite_note-Farmahin2012-13">[13]</a><a href="#cite_note-Farmahin2013a-41">[41]</a><a href="#cite_note-Farmahin2014-21">[21]</a><a href="#cite_note-Herve2010a-42">[42]</a><a href="#cite_note-Herve2010b-43">[43]</a> When screened for their ability to induce aryl hydrocarbon hydroxylase (AHH) activity, dioxins with chlorine atoms at a minimum of three out of the four lateral ring positions, and with at least one non-chlorinated ring position are the most active<a href="#cite_note-Poland1973-44">[44]</a>. Of the dioxin-like PCBs, non-ortho congeners are the most toxicologically active, while mono-ortho PCBs are generally less potent<a href="#cite_note-McFarland1989-45">[45]</a><a href="#cite_note-Safe1994-9">[9]</a>. Chlorine substitution at ortho positions increases the energetic costs of assuming the coplanar conformation required for binding to the AHR <a href="#cite_note-McFarland1989-45">[45]</a>. Thus, a smaller proportion of mono-ortho PCB molecules are able to bind to the AHR and elicit toxic effects, resulting in reduced potency of these congeners. Other PCB congeners, such as di-ortho substituted PCBs, are very weak AHR agonists and do not likely contribute to dioxin-like effects <a href="#cite_note-Safe1994-9">[9]</a>. <ul> <li>Contrary to studies of birds and mammals, even the most potent mono-ortho PCBs bind to AhRs of fishes with very low affinity, if at all (Abnet et al 1999; Doering et al 2014; 2015; Eisner et al 2016; Van den Berg et al 1998).</li> </ul> The role of the AHR in mediating the toxic effects of planar hydrophobic contaminants has been well studied, however the endogenous role of the AHR is less clear <a href="#cite_note-Okey2007-1">[1]</a>. Some endogenous and natural substances, including prostaglandin PGG2 and the tryptophan derivatives indole-3-carbinol, 6-formylindolo[3,2-b]carbazole (FICZ) and kynurenic acid can bind to and activate the AHR. <a href="#cite_note-Fujii2010-6">[6]</a><a href="#cite_note-Omie2011-46">[46]</a><a href="#cite_note-Swed2010-47">[47]</a><a href="#cite_note-Diani2011-48">[48]</a><a href="#cite_note-Wincent2012-49">[49]</a> The AHR is thought to have important endogenous roles in reproduction, liver and heart development, cardiovascular function, immune function and cell cycle regulation <a href="#cite_note-Baba2005-50">[50]</a><a href="#cite_note-Denison2011-38">[38]</a><a href="#cite_note-Fernandez1995-51">[51]</a><a href="#cite_note-Ichihara2007-52">[52]</a><a href="#cite_note-Lahvis2000-53">[53]</a><a href="#cite_note-Mimura1997-54">[54]</a><a href="#cite_note-Omie2011-46">[46]</a><a href="#cite_note-Schmidt1996-55">[55]</a><a href="#cite_note-Thack2002-56">[56]</a><a href="#cite_note-Zhang2010-57">[57]</a> and activation of the AHR by DLCs may therefore adversely affect these processes.

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<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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AOPWiki 2025-05-15T10:42:07

2026-02-25T04:39:30