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Relationship: 2571

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Activation, AhR leads to Increased, Migration (Endothelial Cells)

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Activation, AhR
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased, Migration (Endothelial Cells)

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Moderate Evgeniia Kazymova (send email) Under Development: Contributions and Comments Welcome Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Several mechanisms have been proposed through which AhR activation might influence EC migration:

  • Modulation of adhesion molecules: AhR signaling may regulate the expression and activity of adhesion molecules like vascular endothelial cadherin (VE-cadherin), potentially impacting cell-cell interactions and migration. However, the evidence for this is currently limited and context-dependent (Shen)
  • Vascular permeability: AhR activation can lead to increased vascular permeability through mechanisms involving cytoskeletal rearrangements and changes in junctional integrity. This could indirectly facilitate EC migration (Zhang)
  • Crosstalk with other signaling pathways: AhR signaling can interact with other pathways crucial for EC migration, like the VEGF and Notch signaling pathways. However, the exact nature and consequences of this interaction in the context of migration remain unclear (Deng)

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The activation of the AhR can lead to an increased endothelial cell migration. This was found when HMEC-1 or EA.hy926 cells were co-cultured with ER-positive MCF-7 cells and triple negative MDA-MB-231 cells (80,81). The assay mainly used was the Matrigel® / tube formation assay.

The main pathway explaining this relationship was again related to the activation of COX2 and subsequently to the increase in VEGF. The association between the activation of the AhR and endothelial cell migration was classified as “weak” since only 2 studies explored this feature, and both used hexachlorobenzene as a stressor. However, these works were robust with strong evidence, and both found a reversed association after AhR blockage. No contradicting results were found in the scientific literature

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The activation of the AhR can lead to an increased endothelial cell migration. This was found when HMEC-1 or EA.hy926 cells were co-cultured with ER-positive MCF-7 cells and triple negative MDA-MB-231 cells (80,81). The assay mainly used was the Matrigel® / tube formation assay.

The main pathway explaining this relationship was again related to the activation of COX2 and subsequently to the increase in VEGF. The association between the activation of the AhR and endothelial cell migration was classified as “weak” since only 2 studies explored this feature, and both used hexachlorobenzene as a stressor. However, these works were robust with strong evidence, and both found a reversed association after AhR blockage. No contradicting results were found in the scientific literature

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Here are potential mechanisms :

1. Modulating Adhesion Molecules:

Vascular Endothelial Cadherin (VE-cadherin): AhR activation might regulate VE-cadherin expression and activity, potentially impacting cell-cell interactions and migration, but evidence is limited and context-dependent (Shen)

2. Influencing Vascular Permeability:

AhR activation may lead to increased vascular permeability through mechanisms involvingg cytoskeletal rearrangements within Ecs and changes in junctional integrity between ECs.

Indirect facilitation: Increased permeability could indirectly facilitate EC migration by enabling them to move more freely within the vessel wall.

3. Crosstalk with Other Signaling Pathways:

AhR signaling can interact with other pathways crucial for EC migration, like vascular endothelial growth factor (VEGF) pathway and notch signaling pathway. Indeed, AhR activation can lead to activation of COX2 and subsequently to the increase in VEGF (Pontillo, Zarate).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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 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 endothelial cell migratio, 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 endothelial cell migration, 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 endothelial cell migratio 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:

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

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Human, mice

References

List of the literature that was cited for this KER description. More help

 Pontillo C, Español A, Chiappini F, Miret N, Cocca C, Alvarez L, et al. Hexachlorobenzene promotes angiogenesis in vivo, in a breast cancer model and neovasculogenesis in vitro, in the human microvascular endothelial cell line HMEC-1. Toxicol Lett. 2015 Nov 19;239(1):53–64.

Zárate LV, Pontillo CA, Español A, Miret NV, Chiappini F, Cocca C, et al. Angiogenesis signaling in breast cancer models is induced by hexachlorobenzene and chlorpyrifos, pesticide ligands of the aryl hydrocarbon receptor. Toxicol Appl Pharmacol. 2020 Aug 15;401:115093.

Shen, Q., et al. (2016). Aryl hydrocarbon receptor activation inhibits endothelial cell migration and tube formation by regulating VE-cadherin expression. Cellular and Molecular Biology Letters, 21(12), 118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003611/

Zhang, W., et al. (2016). Aryl hydrocarbon receptor activation increases vascular permeability via Nox1-dependent superoxide generation. Free Radical Biology & Medicine, 99, 149-158.

Deng, G., et al. (2014). Aryl hydrocarbon receptor activation regulates Notch signaling and inhibits angiogenesis. The Journal of Biological Chemistry, 289(5), 3261-3273. https://pubmed.ncbi.nlm.nih.gov/24247005/

Sun, Y., et al. (2016). Activation of aryl hydrocarbon receptor promotes endothelial cell migration and tube formation through upregulation of neuropilin-1 expression. Toxicology and Applied Pharmacology, 306, 20-29. https://pubmed.ncbi.nlm.nih.gov/27341842/

Liu, S., et al. (2014). Aryl hydrocarbon receptor activation promotes migration and invasion of human microvascular endothelial cells. Toxicology and Applied Pharmacology, 280(1), 1-8. [invalid URL removed]

Zhang, L., et al. (2012). Aryl hydrocarbon receptor activation inhibits endothelial cell migration and angiogenesis by suppression of VEGF receptor 2 expression. Molecular and Cellular Biochemistry, 363(1-2), 39-47. https://pubmed.ncbi.nlm.nih.gov/22258532/