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Relationship: 2570
Title
Activation, AhR leads to Increased, Motility
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Activation of the AhR leading to metastatic breast cancer | adjacent | High | Louise Benoit (send email) | Under Development: Contributions and Comments Welcome | Under Development |
Taxonomic Applicability
| Term | Scientific Term | Evidence | Link |
|---|---|---|---|
| Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
| Sex | Evidence |
|---|---|
| Mixed | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| Adults |
Key Event Relationship Description
The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor known for its role in responding to environmental pollutants, such as dioxins and polycyclic aromatic hydrocarbons (PAHs). While the primary functions of AhR have been extensively studied in the context of xenobiotic metabolism and detoxification, emerging evidence suggests its involvement in cellular processes, including cell motility. The precise mechanisms linking AhR activation to increased cell motility are still an area of active research, and findings may vary depending on cell types and contexts. Here are some potential mechanisms:
- AhR-Mediated Gene Expression: AhR, upon ligand binding, translocates into the nucleus and forms a complex with its co-factors. This complex then binds to specific DNA sequences known as xenobiotic response elements (XREs). AhR activation can lead to the transcriptional regulation of genes involved in cell motility. For instance, AhR may regulate the expression of genes associated with cytoskeletal dynamics, cell adhesion, and migration.
- Interaction with Signaling Pathways: AhR activation may modulate the activity of kinases or other signaling molecules involved in cell motility pathways. This cross-talk can impact cellular processes like cytoskeletal rearrangement and focal adhesion dynamics.
- Influence on Cytoskeletal Dynamics: AhR activation could influence the expression of genes involved in cytoskeletal dynamics, affecting processes like actin polymerization, lamellipodia formation, and filopodia extension that are integral to cell motility. AhR signaling can modulate the actin cytoskeleton, the protein network responsible for cell shape and movement (Diry). Changes in actin organization and dynamics can promote the formation of cellular protrusions (like lamellipodia and filopodia), driving cell migration.
- AhR and microenvironment: Studies demonstrate that AhR activation can increase the expression and activity of MMPs, enzymes capable of degrading extracellular matrix (ECM) (Villano). This degradation facilitates cancer cell mobility by disrupting the structural barriers surrounding them.
- Inflammatory Responses: Inflammatory signals can influence cell motility, and AhR activation may contribute to changes in the tumor microenvironment that affect the migratory behavior of cancer cells.
- Epithelial-to-Mesenchymal Transition (EMT): AhR activation has been associated with EMT, a process linked to increased cell motility (mulero). AhR-induced EMT may contribute to the acquisition of a more motile and invasive phenotype in certain cell contexts. For instance, AhR activation can lead to the downregulation of E-cadherin, a critical protein in maintaining cell-cell adhesion. This reduction in E-cadherin weakens the connections between cells, promoting individual cell movement and contributing to loss of tissue integrity (ikuta).
Evidence Collection Strategy
Evidence Supporting this KER
The activation of the AhR can modulate cell motility in different types of breast cancers such as: ER-positive cells lines (MCF-7, T-47D, ZR-75–1), triple negative (MDA-MB-231, MDA-MB-435, HS-578-T, SUM149), and cells overexpressing the Her2 (SK-BR-3) (Goode et al., 2013 Dec 15, Regan Anderson et al., 2018, Parks et al., 2014 Nov, Pontillo et al., 2011 Apr, Qin et al., 2011 Oct 20, Nguyen et al., 2016 Nov 15, Novikov et al., 2016 Nov, Miret et al., 2016 Jul, Shan et al., 2020 Nov, Dwyer et al., 2021 Feb, Narasimhan et al., 2018 May 7, Hsieh et al., 2012 Feb). Activation of the AhR with TCDD, butyl-benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, and benzo[a]pyrene can promote cell migration in different assays (Parks et al., 2014 Nov, Pontillo et al., 2011 Apr, Qin et al., 2011 Oct 20, Novikov et al., 2016 Nov, Miret et al., 2016 Jul, Shan et al., 2020 Nov, Narasimhan et al., 2018 May 7, Hsieh et al., 2012 Feb). On the other hand, the use of AhR antagonists, AhR silencing or AhR knockout reversed this effect (Goode et al., 2013 Dec 15, Regan Anderson et al., 2018, Parks et al., 2014 Nov, Pontillo et al., 2011 Apr, Qin et al., 2011 Oct 20, Novikov et al., 2016 Nov, Shan et al., 2020 Nov, Narasimhan et al., 2018 May 7, Hsieh et al., 2012 Feb). The most frequently used assays for evaluating cell migration were the scratch wound assay and the transwell chamber assay. Only three works evaluated the dose–response concordance of AhR activation with stressors and cell migration (Pontillo et al., 2011 Apr, Miret et al., 2016 Jul, Shan et al., 2020 Nov). The evidence was therefore classified as “moderate”.
Biological Plausibility
Downregulation of cell adhesion molecules: AhR activation can lead to the suppression of E-cadherin expression, a crucial protein maintaining cell-cell adhesion (Ikuta). This weakening of intercellular connections promotes individual cell movement, potentially contributing to loss of tissue integrity and increased motility.
Upregulation of matrix metalloproteinases (MMPs): Studies show that AhR activation can enhance the expression and activity of MMPs (Liu). These enzymes degrade the extracellular matrix (ECM), which acts as a physical barrier for cell movement. Increased MMP activity facilitates ECM breakdown, allowing cancer cells to move more freely and potentially contributing to invasion.
Modulation of cytoskeletal dynamics: AhR signaling has been shown to influence the actin cytoskeleton, a network of protein filaments responsible for cell shape and movement (Diry). Changes in actin organization and dynamics can lead to the formation of cellular protrusions like lamellipodia and filopodia, structures crucial for cell migration.
Epithelial-to-mesenchymal transition (EMT): AhR activation has been implicated in inducing EMT, a process where epithelial cells lose their characteristic features and acquire a more motile, mesenchymal phenotype (Mulero). EMT-associated changes in cell adhesion, matrix remodeling, and cytoskeleton restructuring create a more motile and invasive cell population.
Empirical Evidence
In Vitro Studies:
Several studies report that exposing cancer cell lines to AhR agonists (activators), like environmental pollutants (TCDD) or polycyclic aromatic hydrocarbons (PAHs), leads to increased cell migration and invasion in assays mimicking the invasion process (Diry, Liu). These studies often showcase mechanistic pathways involved, such as downregulation of E-cadherin (adhesion molecule) or upregulation of MMPs (matrix-degrading enzymes), potentially facilitating movement and breaching barriers (Ikuta, Jin)
Uncertainties and Inconsistencies
While the potential connection between AhR activation and increased cell motility in cancer is intriguing, several limitations and uncertainties necessitate further exploration:
1. Specificity and Context Dependence:
Most studies employ potent AhR agonists like environmental pollutants, which may not reflect the effects of endogenous ligands or environmental exposures at lower levels. These endogenous ligands and lower exposure levels might have different effects on cell motility depending on the specific context. Moreover, studies often focus on specific cancer cell lines, raising questions about their generalizability to diverse cancer types and patient populations. The response to AhR activation might vary significantly depending on the specific genetic and molecular makeup of different cancer cells.
2. Lack of Robust In Vivo Evidence:
Limited in vivo data currently exists to confirm observations from in vitro studies within the complex tumor microenvironment. In vivo models can better capture the interplay of various factors influencing cell motility, potentially revealing discrepancies compared to isolated cell line studies.
3. Conflicting Findings and Need for Further Mechanistic Understanding:
Some studies report AhR activation suppressing or having no effect on cell motility, highlighting the need for further investigation and a deeper understanding of the context-dependent effects and the specific mechanisms at play.The complete picture of how AhR signaling pathways influence cell motility and how these effects translate to the complex tumor microenvironment remains unclear. More research is needed to elucidate the specific downstream targets and signaling cascades involved.
4. Challenges in Translating In Vitro Findings to Clinical Applications:
Even if a robust link between AhR activation and increased cell motility is established, translating this knowledge into clinical applications presents significant challenges. Targeting the AhR pathway for therapeutic purposes is complex due to its diverse physiological roles and potential for unintended side effects.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Human, breast cancer cell lines
References
Mulero-Navarro, S., & Fernandez-Salguero, P. M. (2016). New Trends in Aryl Hydrocarbon Receptor Biology. Frontiers in Cell and Developmental Biology, 4, 45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869068/
Liu, S., et al. (2016). Aryl hydrocarbon receptor activation promotes migration and invasion of human prostate cancer cells by regulating matrix metalloproteinase-2 expression. Oncogene, 35(24), 3230-3242. https://pubmed.ncbi.nlm.nih.gov/26504490/
Jin, H., et al. (2014). Aryl hydrocarbon receptor enhances the migration and invasion of cervical cancer cells through the upregulation of MMP-9 expression via the PI3K/Akt signaling pathway. International Journal of Oncology, 44(5), 1517-1524. https://pubmed.ncbi.nlm.nih.gov/24611264/
Ikuta, T., Kawajiri, K. (2006). Zinc finger transcription factor Slug is a novel target gene of aryl hydrocarbon receptor. Experimental Cell Research, 312(17), 3585–3594. https://pubmed.ncbi.nlm.nih.gov/16949563/
Villano, C. M., Murphy, K. A., & White, L. A. (2006). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) activity and cell migration in human keratinocytes. Toxicology and Applied Pharmacology, 215(3), 216–225. https://pubmed.ncbi.nlm.nih.gov/16781816/
Diry, M., Tomkiewicz, C., Koehle, C., Coumoul, X., Bock, K. W., Barouki, R., & Transy, C. (2005). Activation of the dioxin/aryl hydrocarbon receptor (AhR) modulates cell plasticity through a Rho-ROCK-myosin-dependent pathway. Oncogene, 25(19), 5570–5574. https://pubmed.ncbi.nlm.nih.gov/16568080/
Mulero-Navarro, S., & Fernandez-Salguero, P. M. (2016). New Trends in Aryl Hydrocarbon Receptor Biology. Frontiers in Cell and Developmental Biology, 4, 45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869068/
Parks AJ, Pollastri MP, Hahn ME, Stanford EA, Novikov O, Franks DG, et al. In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo. Mol Pharmacol. 2014 Nov;86(5):593–608.
47. Pontillo CA, García MA, Peña D, Cocca C, Chiappini F, Alvarez L, et al. Activation of c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration by hexachlorobenzene in MDA-MB-231 human breast cancer cell line. Toxicol Sci Off J Soc Toxicol. 2011 Apr;120(2):284–96.
48. Qin X-Y, Wei F, Yoshinaga J, Yonemoto J, Tanokura M, Sone H. siRNA-mediated knockdown of aryl hydrocarbon receptor nuclear translocator 2 affects hypoxia-inducible factor-1 regulatory signaling and metabolism in human breast cancer cells. FEBS Lett. 2011 Oct 20;585(20):3310–5.
49. Nguyen CH, Brenner S, Huttary N, Atanasov AG, Dirsch VM, Chatuphonprasert W, et al. AHR/CYP1A1 interplay triggers lymphatic barrier breaching in breast cancer spheroids by inducing 12(S)-HETE synthesis. Hum Mol Genet. 2016 Nov 15;25(22):5006–16.
50. Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A, Landesman E, et al. An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells. Mol Pharmacol. 2016 Nov;90(5):674–88.
51. Miret N, Pontillo C, Ventura C, Carozzo A, Chiappini F, Kleiman de Pisarev D, et al. Hexachlorobenzene modulates the crosstalk between the aryl hydrocarbon receptor and transforming growth factor-β1 signaling, enhancing human breast cancer cell migration and invasion. Toxicology. 2016 Jul 29;366–367:20–31.
52. Shan A, Leng L, Li J, Luo X-M, Fan Y-J, Yang Q, et al. TCDD-induced antagonism of MEHP-mediated migration and invasion partly involves aryl hydrocarbon receptor in MCF7 breast cancer cells. J Hazard Mater. 2020 Nov 5;398:122869.
53. Dwyer AR, Kerkvliet CP, Krutilina RI, Playa HC, Parke DN, Thomas WA, et al. Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling. Mol Cancer Res MCR. 2021 Feb;19(2):329–45.
54. Narasimhan S, Stanford Zulick E, Novikov O, Parks AJ, Schlezinger JJ, Wang Z, et al. Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor. Int J Mol Sci. 2018 May 7;19(5):1388.
55. Hsieh T-H, Tsai C-F, Hsu C-Y, Kuo P-L, Lee J-N, Chai C-Y, et al. Phthalates induce proliferation and invasiveness of estrogen receptor-negative breast cancer through the AhR/HDAC6/c-Myc signaling pathway. FASEB J Off Publ Fed Am Soc Exp Biol. 2012 Feb;26(2):778–87.