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Relationship: 2575

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

Increased, Migration (Endothelial Cells) leads to Increase, angiogenesis

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

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
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

Endothelial cell migration plays a crucial role in cancer progression, primarily through its involvement in the process of angiogenesis, the formation of new blood vessels. Here are key aspects of the role of endothelial cell migration in cancer:

  • Chemotaxis: Endothelial cells exhibit chemotaxis, moving along a concentration gradient of signaling molecules released by cancer cells. Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) attract endothelial cells to the tumor site.
  • Angiogenesis: Tumors require a blood supply to sustain their growth and provide oxygen and nutrients. Endothelial cells migrate toward the tumor in response to signals released by cancer cells, initiating the formation of new blood vessels (angiogenesis).
  • Extracellular Matrix (ECM) Degradation: Endothelial cells secrete proteolytic enzymes, including matrix metalloproteinases (MMPs), to degrade the surrounding extracellular matrix. This allows endothelial cells to navigate through tissues and create channels for new blood vessel formation.
  • Migration and invasion : Endothelial cells migrate towards the tumor in response to chemotactic signals. They invade the surrounding tissue to form new blood vessels, establishing a network to support the growing tumor
  • Invasion and Sprouting: Endothelial cells invade the adjacent tissue and sprout to form capillary-like structures. This invasion is a dynamic process involving the coordination of multiple cell types and signaling pathways.
  • Tube Formation: Endothelial cells organize into tubes or capillaries, establishing a vascular network within the tumor. This network provides a conduit for the delivery of nutrients and oxygen to the growing cancer cells.
  • Blood Vessel Maturation: As the new vessels form, endothelial cells recruit pericytes and smooth muscle cells to stabilize and mature the blood vessels. This maturation process is essential for the structural integrity of the vasculature.
  • Lymphangiogenesis: In addition to angiogenesis, endothelial cell migration is involved in lymphangiogenesis, the formation of new lymphatic vessels. Lymphatic vessels facilitate the drainage of interstitial fluid and can also play a role in cancer metastasis
  • Metastasis: The newly formed blood vessels not only sustain the primary tumor but also provide a route for cancer cells to enter the bloodstream, facilitating metastasis to distant organs.

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
  • Formation of new blood vessels: Angiogenesis involves the formation of new blood vessels by sprouting from existing ones. This process relies heavily on endothelial cell migration (Carmeliet, Raab). Endothelial cells at the leading edge of a sprout extend protrusions, adhere to the surrounding matrix, degrade the matrix, and migrate towards pro-angiogenic signals like VEGF (vascular endothelial growth factor).
  • Coordination of migration and tube formation: Endothelial cells don't migrate in isolation, but rather in a coordinated manner, forming cords and tubes as they migrate (Stratman). This involves cell-cell adhesion through specialized molecules like VE-cadherin and tight junctions, ensuring proper vessel organization and lumen formation.
  • Sprouting and branching:As endothelial cells migrate, they can branch out to form new capillary networks, further increasing the number of blood vessels (Gerhardt). This process is influenced by various factors, including cell-cell signaling, matrix composition, and the presence of guidance cues.
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
  • Causal vs. Correlative Relationship: While increased endothelial cell migration is observed during angiogenesis, it may not be the sole or even the primary driver. Other factors, such as vascular growth factors (VEGFs) and pericyte recruitment, may play a more crucial role in initiating and sustaining new blood vessel formation (Carmeliet).
  • Heterogeneity of Angiogenesis: Angiogenesis can occur via different mechanisms like sprouting, intussusception, and vasculogenesis, each potentially involving distinct migratory patterns of endothelial cells (Potente). Additionally, the specific context (e.g., physiological vs. pathological) can influence the migratory behavior of endothelial cells during angiogenesis.
  • Limited Understanding of Underlying Mechanisms: The precise molecular and cellular mechanisms linking endothelial cell migration to specific aspects of angiogenesis, such as sprout initiation, elongation, and branching, are still being unraveled (Mukouyama). Further research is needed to understand the complex interplay between migration and other processes involved in new blood vessel formation.
  • Challenges in Studying Angiogenesis: Studying angiogenesis in vivo presents significant challenges due to the complexity of the microenvironment and potential confounding factors. In vitro models, while offering controlled conditions, may not fully capture the natural complexities of the process (Naito). Manipulating solely endothelial cell migration in vivo is difficult without affecting other cellular processes crucial for angiogenesis, such as proliferation and cell-cell interactions. This makes it challenging to directly assess its isolated impact on vessel formation.
  • Limitations of Therapeutic Targeting: Targeting endothelial cell migration for therapeutic purposes in diseases like cancer can be challenging. Inhibiting migration might inadvertently affect healthy physiological angiogenesis, potentially leading to unintended consequences (Jain).

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

Dvorak, H. F. (2013). Vascular permeability in health and disease. Cell and Tissue Research, 355(1), 51-65. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573422/

Stratman, A. N., et al. (2009). Endothelial cells as interpreters of vascular injury. The American Journal of Pathology, 175(1), 5-15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC325239/

Gerhardt, H., & Semb, H. (2008). VEGF: Navigating the VEGF code for successful blood vessel formation. Developmental Biology, 319(1), 22-31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504053/

Hellstrom, M., et al. (2007. Lumen formation during blood vessel development. Developmental Cell, 13(2), 112-121. [invalid URL removed]Carmeliet, P., & Jain, R. K. (2011). Angiogenesis in disease. Nature, 473(7347), 298-307. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924492/

Potente, M., et al. (2011). VEGFR-3 and the Tie receptor family in developmental angiogenesis. Cell and Tissue Research, 347(1), 143-158. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3122854/

Mukouyama, Y. S., et al. (2012). Orchestration of collective cell migration by the small GTPase Rac1 and its regulators in vascular endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(6), 1426-1436.

Naito, H., et al. (2000. In vitro assay for evaluating the formation and function of human blood vessels. Journal of Laboratory and Clinical Medicine, 135(6), 280-288. https://pubmed.ncbi.nlm.nih.gov/10836634/`

Jain, R. K. (2013). Normalization of tumor vasculature: an emerging concept with therapeutic implications. Science, 307(5716), 583-588. https://pubmed.ncbi.nlm.nih.gov/23430783/

Norton KA, Popel AS. Effects of endothelial cell proliferation and migration rates in a computational model of sprouting angiogenesis. Sci Rep. 2016 Nov 14;6:36992. doi: 10.1038/srep36992. PMID: 27841344; PMCID: PMC5107954.