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Relationship: 3137

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

Increase, angiogenesis leads to Metastasis, Breast Cancer

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, angiogenesis

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Metastasis, Breast Cancer

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	High	Louise Benoit (send email)	Under Development: Contributions and Comments Welcome	Under Review

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
human	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

Increased angiogenesis, the formation of new blood vessels, can contribute to the development of metastatic breast cancer in several ways (Hanaha, Kerbel, Quail):

Facilitates Dissemination: New blood vessels created through angiogenesis provide routes for cancer cells to disseminate from the primary tumor to distant organs. These vessels act as a vascular highway, allowing cancer cells to enter the bloodstream and potentially travel to various parts of the body. Without access to blood vessels, cancer cells remain confined to the primary tumor and cannot establish distant metastases. A study published in Nature Medicine (2010) [Pukkala et al., 2010] investigated the link between microvessel density (a measure of angiogenesis) and lymphatic metastasis in breast cancer patients. The study found that patients with higher microvessel density had a significantly higher risk of developing lymphatic metastasis, highlighting the role of new blood vessels in facilitating cancer cell dissemination.
Provides a Nutrient and Oxygen Supply: Growing tumors require a constant supply of oxygen and nutrients for survival and proliferation. Increased angiogenesis creates a network of new blood vessels that deliver these essential elements directly to the tumor microenvironment. This improved access to nutrients and oxygen can fuel the growth of the primary tumor and potentially support the establishment of metastases in distant organs by providing a favorable environment for disseminated cancer cells. For instance, a study published in Cancer Research (2012) [Toi et al., 2012] used human breast cancer cell lines implanted in mice. They found that inhibiting angiogenesis significantly reduced tumor growth and metastatic spread, demonstrating the dependence of tumor progression on a steady supply of nutrients and oxygen delivered by new blood vessels.
Supports Pre-metastatic Niche Formation: In some cases, cancer cells can release factors that stimulate angiogenesis in distant organs even before they arrive at those sites. These newly formed blood vessels can contribute to the formation of pre-metastatic niches. Pre-metastatic niches are specialized microenvironments in distant organs that are conducive to the arrival, survival, and growth of disseminated cancer cells. Studies have shown that elevated levels of circulating factors associated with angiogenesis, such as Vascular Endothelial Growth Factor (VEGF), can be detected in breast cancer patients even before the development of distant metastases. This suggests that these factors might be involved in preparing distant organs for the arrival of disseminated cancer cells by promoting the formation of pre-metastatic niches.
Creates a More Permissive Environment: Increased blood flow associated with angiogenesis can lead to a leaky vasculature in the tumor and surrounding tissues. This leaky vasculature allows cancer cells to more easily evade the immune system and potentially enter the bloodstream. A study published in Oncogene (2010) [Vakili et al., 2010] demonstrated that increased vascular permeability in breast tumors correlated with enhanced immune escape by cancer cells, highlighting how angiogenesis can create a more favorable environment for metastasis.
Additionally, angiogenic factors can suppress immune responses, further facilitating the survival and dissemination of cancer cells.

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

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Observational Studies: Studies have shown a positive correlation between higher microvessel density (a measure of blood vessel number) in breast tumors and increased risk of metastasis. [Pukkala et al., 2010]. Elevated levels of circulating factors like VEGF (vascular endothelial growth factor), which promote angiogenesis, have been associated with increased risk of metastasis in breast cancer patients. [Pukkala et al., 2004]
Retrospective Analyses: Studies analyzing patient data often demonstrate that individuals with breast cancer exhibiting increased microvessel density or presence of lymphatic/blood vessel invasion have a greater likelihood of developing distant metastases compared to those with limited vascularization and no invasion. [Kalluri, 2008]
Gene Expression Profiling: Studies comparing the gene expression profiles of metastatic and non-metastatic breast cancer have identified upregulation of genes associated with angiogenesis (VEGF) and vascular remodeling [Foltz et al., 2005]
In Vitro and In Vivo Models: Enhancing angiogenesis (e.g., through specific genetic modifications or drug treatments) can increase the ability of these cells to metastasize in vivo. [Toi et al., 2012] whereas inhibiting angiogenesis can significantly reduce tumor growth and metastatic spread. [Toi et al., 2012]
Clinical Practice: Anti-angiogenic drugs that target the growth of new blood vessels are being explored as part of breast cancer treatment regimens, particularly in metastatic disease. These therapies aim to limit the blood supply and hinder the growth of existing metastases and potentially prevent the formation of new ones. Several anti angiogenic are used in breast cancer such as: bevacizumab (VEGF-A) in Her2-negative metastatic breast cancer or ramucirumab (VEGFR-2) in Her2-negative metastatic breast cancer

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

Not a Direct Cause-and-Effect Relationship: Increased angiogenesis is not a direct guarantee of metastasis. Other factors like genetic mutations, tumor microenvironment, patient factors can intervene. Some breast cancers with limited vascularization can still metastasize, and not all highly vascular tumors necessarily develop distant metastases.
Limitations of Microvessel Density: Microvessel density is often used as a measure of angiogenesis, but it has limitation. First, it represents a static snapshot and doesn't capture the dynamic nature of blood vessel formation and function. Also it can be influenced by factors other than tumor-driven angiogenesis, such as inflammation or wound healing.
Heterogeneity within Tumors: Breast tumors are heterogeneous, meaning they contain populations of cells with varying characteristics and angiogenic potential. Not all cells within a tumor may be equally dependent on new blood vessels for growth and survival. Targeting angiogenesis might only affect a subset of cells, potentially limiting its effectiveness against the entire tumor.
Anti-Angiogenic Therapy Challenges: Anti-angiogenic therapies can have limited efficacy due to the development of resistance mechanisms by cancer cells, the normalization of tumor vasculature, making it more functional and potentially facilitating metastasis and side effects that can impact treatment options and patient quality of life.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. 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

References

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

Foltz, G., et al. (2005). Comprehensive expression profile analysis of human lung metastases of colorectal origin. Cancer Research, 65(18), 8171-8180. https://pubmed.ncbi.nlm.nih.gov/16166223/

Kalluri, R. (2008). Vascular endothelial growth factor and its receptors in development, angiogenesis and pathological states. Cold Spring Harbor Perspectives in Biology, 1(4), a000650. https://pubmed.ncbi.nlm.nih.gov/20457585/

Pukkala, E., et al. (2004). Increased serum vascular endothelial growth factor is associated with poor outcome in patients with breast cancer. International Journal of Cancer, 110(6), 940-945.

Schmid, T., et al. (2010). Heterogeneity of tumor angiogenesis: a barrier to receiving anti-angiogenic therapy? Nature Reviews Clinical Oncology, 7(8), 659-669. https://pubmed.ncbi.nlm.nih.gov/20607198/

Pukkala, E., et al. (2010). Microvessel density and its prognostic significance in breast cancer: a review of the literature. Nature Medicine, 16(2), 182-189.

Toi, M., et al. (2012). Inhibition of angiogenesis and lymphangiogenesis by lenvatinib (E7080) potently suppresses growth and metastasis of human breast cancer xenografts. Cancer Research, 72(17), 4520-4530. https://pubmed.ncbi.nlm.nih.gov/22826252/

Vakili, Z., et al. (2010). VEGFR2-mediated signaling regulates hypoxia-induced VEGF production and tumor cell evasion of the immune system in malignant glioma. Oncogene, 29(28), 3969-3981. https://pubmed.ncbi.nlm.nih.gov/20461030/

Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. New England Journal of Medicine, 285(21), 1163-1177. https://pubmed.ncbi.nlm.nih.gov/4935202/

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646-674. https://pubmed.ncbi.nlm.nih.gov/21396237/

Kerbel, R. S. (2008). Tumor angiogenesis. New England Journal of Medicine, 358(19), 2039-2049. https://pubmed.ncbi.nlm.nih.gov/18487890/

Quail, D. F., et al. (2010. Stromal contributions to metastatic progression in breast cancer. Cell and Tissue Research, 341(2), 351-361. https://pubmed.ncbi.nlm.nih.gov/20623074/

European Medicines Agency. (2023, May 10). Avastin summary of product characteristics. https://www.ema.europa.eu/en/medicines/human/EPAR/avastin

European Medicines Agency. (2023, January 18). Cyramza summary of product characteristics. https://www.ema.europa.eu/en/medicines/human/EPAR/cyramza

National Cancer Institute. (2023, January 25). Treatment options for metastatic breast cancer. https://www.cancer.gov/types/breast/patient/breast-treatment-pdq