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Relationship: 2574


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

Increase, Inflammation leads to Increase, angiogenesis

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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 High 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
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

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

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

Likewise, two studies evaluated the specific continuum AhR activation – increased inflammation – increased angiogenesis (Pontillo et al., 2015 Nov 19Zárate et al., 2020 Aug). As previously mentioned, the AhR activation increases inflammation, notably through an increase in COX 2 (Bekki et al., 2015Miller et al., 2005Degner et al., 2009 JanPontillo et al., 2015 Nov 19Zárate et al., 2020 Aug).

COX-2 can promote angiogenesis through an increase in VEGF (Vascular endothelial growth factor) (Harris et al., 2014 Oct 10Kirkpatrick et al., 2002). In a pathologic study characterizing 46 breast cancer specimen using immunochemistry, it was found that the density of microvessels was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03) (Costa et al., 2002 Jun). The relationship between COX-2 and angiogenesis has also been shown in gastric and colorectal cancer (Tsujii et al., 1998 May 29Uefuji et al., 2000 Jan). Indeed, colon carcinoma cells overexpressing COX-2 produce proangiogenic factors (VEGF, bFGF, TBF-β, PDGF, and endothelin-1), and stimulate endothelial migration and the formation of tube vessels. These effects were reversed by an inhibitor (NS-398). In vivo, Diclofenac, a COX-2 inhibitor, decreased angiogenesis in mice presenting a colorectal cancer (Seed et al., 1997 May 1). Likewise, in a murine model of breast cancer, celecoxib (a selective COX-2 inhibitor) reduced metastasis and tumor burden through a decrease of micro vessel density and VEGF (Yoshinaka et al., 2006 DecZhang et al., 2004 Sep). In clinical studies, patients with inflammatory breast cancers have increased levels of genes involved in angiogenesis such as VEGF (Van der Auwera et al., 2004 Dec 1). Patients with an inflammatory breast cancer benefit the most from anti-angiogenic treatment bevacizumab (Pierga et al., 2012 Apr).

The evidence was classified as “moderate” due to the lack of dose response studies.

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

Evidence Supporting this KER

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

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
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


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