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Relationship: 1306

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, Motility leads to Increased, Invasion

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
Estrogen receptor activation leading to breast cancer adjacent Moderate Moderate Brendan Ferreri-Hanberry (send email) Open for adoption
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

Increased cell motility is a crucial factor contributing to increased invasion in various biological processes, including cancer metastasis. Cell motility refers to the ability of cells to move from one location to another, and when this ability is enhanced, it can facilitate the invasion of cells into surrounding tissues.

The relation between cell migration and organ invasion has already been shown (KER-1306, https://aopwiki.org/relationships/1306). Since the 2 are closely linked, most articles studied both cell migration (chemo-tactic) and the capacity to invade the extra-cellular matrix. Cell invasion is indeed defined as the capacity of a cell to migrate and degrade/invade the extracellular matrix. In vitro, this process was evaluated mostly using transwell chamber with Matrigel® and the presence of matrix metalloproteinases (MMP). This effect was found in ER-positive cells, triple negative cell lines and cells overexpressing the Her2.

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

Increased cell motility is a crucial factor contributing to increased invasion in various biological processes, including cancer metastasis. Cell motility refers to the ability of cells to move from one location to another, and when this ability is enhanced, it can facilitate the invasion of cells into surrounding tissues. Here's how increased cell motility leads to increased invasion:

  • Chemotaxis and Chemoattractants: Cells with increased motility are more responsive to chemoattractants (Signaling molecules released by tissues thatt attract and guide cells toward specific locations), allowing them to efficiently navigate through tissue barriers.
  • Enhanced Migration Through Extracellular Matrix (ECM): Increased cell motility is often associated with enhanced secretion of proteolytic enzymes, such as matrix metalloproteinases (MMPs), that degrade the ECM (Egeblad). Cells with higher motility can efficiently squeeze through ECM spaces created by their own proteolytic activity, facilitating invasion into surrounding tissues.
  • Formation of Cellular Protrusions: Highly motile cells often form dynamic structures such as lamellipodia (sheet-like protrusions) and filopodia (finger-like protrusions). These structures increase the surface area of contact between the cell and the surrounding environment, promoting effective movement through tissues.
  • Adhesion to Extracellular Matrix: Motile cells form focal adhesions, dynamic connections between the cell and ECM components. Increased motility enhances the ability of cells to dynamically form and disassemble these adhesions, promoting efficient movement through the ECM (Friedl). Increased motility allows cancer cells to detach from neighboring cells through mechanisms like downregulation of E-cadherin, a key cell adhesion molecule (Friedl). This disrupts the tight junctions holding them together, creating space for individual cells to move.
  • Cytoskeletal Rearrangement: Increased cell motility is often accompanied by dynamic rearrangements of the actin cytoskeleton. Cells with enhanced motility can rapidly change shape, allowing them to navigate through complex tissue environments.
  • Cell-Cell and Cell-ECM Interactions: Motile cells can interact dynamically with neighboring cells, forming transient contacts. Enhanced motility allows cells to engage with ECM components more efficiently, promoting effective migration and invasion.
  • Epithelial to mesenchymal transition (EMT): cell motility increases EMT (Sahai)
  • Intravasion and extravasation: cell with increased motility can enter the bloodstream and then exit the main circulation thus promoting invasion (Kumar).
  • Involvement in Collective Migration: Groups of motile cells can move collectively, promoting invasion as a coordinated front. Enhanced motility of individual cells within the group contributes to the overall invasive potential of the collective migration.
  • Adaptation to Microenvironmental Challenges: Cells with increased motility can better navigate physical barriers within tissues, overcoming challenges posed by the surrounding microenvironment.

 

Increased cell motility is a multifaceted process involving various molecular and cellular mechanisms. In the context of cancer, understanding and targeting these mechanisms are crucial for developing strategies to inhibit tumor invasion and metastasis.

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

Biological plausibility (Egebald, Hodgkinson, Agarwal, Saha, Friedel)

Extracellular Matrix (ECM) Interaction: Cancer cells with enhanced motility often exhibit changes in surface receptors and cytoskeletal dynamics, allowing them to adhere to and move through the ECM more effectively. This is crucial for breaching physical barriers and invading neighboring tissues.

Proteolytic Enzyme Secretion: Highly motile cancer cells often secrete proteolytic enzymes, such as matrix metalloproteinases (MMPs), that break down ECM proteins. This proteolytic activity facilitates the remodeling of the ECM, enabling cancer cells to invade surrounding tissues and enter blood or lymphatic vessels.

Dynamic Cell-Cell and Cell-ECM Interactions: Increased cell motility allows cancer cells to form and disassemble focal adhesions with neighboring cells and the ECM. This dynamic interaction promotes efficient migration and invasion, enabling cancer cells to adapt to the changing microenvironment during invasion.

Chemotaxis and Chemoattractants: Cancer cells with increased motility are more responsive to chemoattractants, signaling molecules that guide cell movement. Chemotaxis allows cancer cells to navigate towards blood vessels, lymphatic vessels, or specific tissues, facilitating invasion into distant organs.

Formation of Cellular Protrusions: Highly motile cancer cells often extend dynamic protrusions like lamellipodia and filopodia. These structures increase the surface area of contact with the surrounding environment, allowing cancer cells to explore and invade tissues efficiently.

Adaptation to Microenvironmental Challenges: Increased motility enables cancer cells to navigate through physical barriers, adapt to varying oxygen levels, and respond to microenvironmental cues. This adaptability is crucial for successful invasion into different organ environments.

Involvement in Collective Migration: Collective migration, where multiple motile cells move as a coordinated front, enhances the invasive potential of a group of cancer cells. Increased motility of individual cells contributes to the overall success of collective invasion.

Survival and Escape from Immune Surveillance: Increased motility allows cancer cells to escape immune surveillance by quickly moving through tissues and avoiding immune responses. This is crucial for the survival of circulating tumor cells during metastasis.

Angiogenesis and Intravasation: Increased motility contributes to the ability of cancer cells to intravasate into vessels. It is also associated with angiogenesis, the formation of new blood vessels, providing a route for cancer cells to enter the bloodstream.

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

While there is substantial empirical evidence supporting the notion that increased cell motility contributes to increased organ invasion, it is important to acknowledge uncertainties and inconsistencies in the literature. These uncertainties stem from the complexity of biological systems, the heterogeneity of tumors, and variations in experimental methodologies. Here are some potential uncertainties and inconsistencies:

  • Tumor Heterogeneity: Variability in motility within a tumor may lead to inconsistent observations, with some regions demonstrating enhanced invasion while others do not (Friedl, Valastyan).
  • Context Dependency: The role of increased cell motility in invasion may vary depending on the tumor type, microenvironment, and organ of interest (Friedl, Valastyan). For example, breast and pancreatic cancers exhibit a strong dependence on motility for invasion, while gliomas (brain tumors) infiltrate surrounding tissues through a different mechanism known as amoeboid movement, potentially minimizing the role of classical motility (Friedl, Valastyan).
  • In Vitro vs. In Vivo Discrepancies: Increased motility observed in cell culture may not translate to enhanced invasion in complex in vivo settings, possibly due to differences in the microenvironment and additional factors influencing invasion. For example, The ECM composition in model systems often doesn't fully capture the diverse components and architecture found in real tumors, potentially influencing cell motility and invasion differently (Hodgkinson).
  • Divergent Experimental Models: Varied experimental models, including xenografts, organoids, and in vitro cultures, may produce different outcomes. For instance, Most preclinical models lack a functional immune system, neglecting the role of immune cells in either aiding or hindering invasion (Gentezl).
  • Dynamic Tumor Microenvironment: The tumor microenvironment is dynamic, and factors such as hypoxia, inflammation, and immune responses can influence invasion. Interactions with the dynamic microenvironment may modulate the relationship between cell motility and invasion, introducing complexities and uncertainties.
  • Adaptation and Compensation: Over time, compensatory mechanisms may mask the direct impact of increased motility on invasion, leading to inconsistencies in experimental outcomes.
  • Genetic and Epigenetic Variations: The contribution of increased motility to invasion may be influenced by other genetic or epigenetic alterations, introducing variability in experimental outcomes.
  • Timing of Measurements: Assessments conducted at different stages of tumor progression may yield varied results, and the temporal dynamics of increased motility and invasion need to be considered.
  • Artifactual Observations: Inconsistencies may arise from variations in the accuracy and sensitivity of experimental methods used to assess motility and invasion.

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

Hodgkinson, P., et al. (2012). Tumor microenvironment and the efficacy of anticancer treatment. Cancer Treatment Reviews, 38(3), 231-239. https://pubmed.ncbi.nlm.nih.gov/21727232/

Gentzel, D. B., et al. (2016). Transforming the cancer research paradigm: investigating the role of the tumor microenvironment in cancer progression. The Journal of Clinical Investigation, 126(8),

Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Trends in Cell Biology, 12(3), 104-110. https://pubmed.ncbi.nlm.nih.gov/11850277/

Yurchenco, P. D., & Patton, B. T. (2009). Basement membrane assembly and function. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1790(10), 473-489. https://pubmed.ncbi.nlm.nih.gov/19436234/

Agarwal, R., et al. (2013). EMT and Cancer Cell Migration: Roles of TGF-β and Rho Kinase Signaling. Cancers (Basel) 5(2), 820-830. [invalid URL removed]

Wiseman, B. S., et al. (2003. Conditional loss of p53 in vivo allows for malignant progression of mammary epithelial cells. Proceedings of the National Academy of Sciences, 100(21), 12097-12102. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC227137/

Valastyan, S., & Weinberg, R. A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Journal of Clinical Oncology, 29(15), 1976-1982. https://pubmed.ncbi.nlm.nih.gov/21502471/

Gupta, S., & Nguyen, D. X. (2005. Intracellular signaling in breast cancer metastasis. Cancer Metastasis Reviews, 24(2), 155-172. [invalid URL removed]

Sahai, E., & Astsaterova, I. (2018. YAP/TA

Friedl, P., & Gilmour, D. (2009). Collective cell migration in morphogenesis, regeneration, and cancer. Nature Reviews Molecular Cell Biology, 10(8), 445-457. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721204/

Egeblad, M., & Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Trends in Cell Biology, 12(3), 104 110. https://pubmed.ncbi.nlm.nih.gov/11850277/

Friedl, P., & Weigelin, B. (2008. Interstitial cell migration and cell-matrix interactions in metastasis. Nature Cell Biology, 10(11), 1161-1169. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587008/

Sahai, E., & Srivastava, A. (2007). Metastasis and EMT: thrust and parry in the cell biology arena. Nature Cell Biology, 9(3), 238-245. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702212/

Kumar, V. (2002. Intravascular navigation and extravasation of tumor cells. Cancer Metastasis Reviews, 21(1-2), 17-33. [invalid URL removed]