API

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Relationship: 2573

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, Inflammation leads to Increased, Invasion

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Inflammation
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increased, Invasion

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 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
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
Adult 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 inflammation is intricately linked to various processes that can promote and facilitate cell invasion, particularly in the context of cancer (Hanahan) :

  • Release of Pro-Inflammatory Cytokines (Hanahan): Inflammatory cells, such as macrophages and neutrophils, release pro-inflammatory cytokines (e.g., interleukin-6, tumor necrosis factor-alpha). These cytokines can activate signaling pathways that promote cell survival, proliferation, and migration. Pro-inflammatory cytokines can induce the expression of matrix metalloproteinases (MMPs), enzymes that degrade the extracellular matrix (ECM). ECM degradation is a crucial step for cancer cells to invade surrounding tissues (Lee, Manicone).
  • Recruitment of Immune Cells: Inflammation leads to the recruitment of immune cells to the site of inflammation. These cells release various factors that create an environment conducive to cell invasion. Tumor-associated macrophages (TAMs), for example, can release growth factors and cytokines that stimulate cancer cell invasion (Pan, Lin).
  • Angiogenesis: Inflammatory cells release molecules like epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) stimulate cell proliferation and migration, potentially promoting invasion (Shaik).
  • Epithelial-Mesenchymal Transition (EMT): Inflammatory signals can induce EMT, a process where cancer cells acquire mesenchymal characteristics, including increased motility and invasiveness. During EMT, cancer cells lose their cell-cell adhesion properties and gain the ability to invade surrounding tissues and enter the bloodstream (Suarez, Lopze).
  • Activation of Nuclear Factor-kappa B (NF-κB): NF-κB is a transcription factor that plays a central role in inflammatory responses. It regulates the expression of genes involved in cell survival, proliferation, and inflammation. NF-κB activation in cancer cells can enhance their invasive potential by promoting the expression of genes associated with invasion and metastasis (Liu, Zhang)).
  • Acitvation COX 2 : The mechanism of action of COX-2 are consensual. COX-2 promotes cell invasion through upregulation of MMPs (notably 2 and 9) (Takahashi et al., 1999 Oct 22, Sivula et al., 2005 Feb, Larkins et al., 2006 Jul). Moreover, COX-2 could also activate the urokinase plasminogen activator (uPA) which degrades the basal membrane of epithelia (Singh et al., 2005 May, Takahashi et al., 1999 Oct 22, Larkins et al., 2006 Jul, Guyton et al., 2000 Mar).
  • Interaction with Stromal Cells: Inflammatory signals can influence the interactions between cancer cells and stromal cells in the tumor microenvironment. Fibroblasts, for example, can be activated by inflammation to secrete factors that enhance tumor cell invasion and migration (Davidson).

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
  • Molecular and cellular evidence: Inflammatory mediators like cytokines activate signaling pathways like NF-κB, MAPK, and PI3K/Akt, promoting cell proliferation, survival, migration, and invasion (Karin, Hanahan). These pathways can upregulate the expression of genes involved in cell movement and matrix degradation, facilitating invasion. Inflammatory stimuli can induce the production of MMPs, enzymes that break down extracellular matrix (ECM) components. Degradation of ECM creates pathways for cells to migrate and invade surrounding tissues (Whiteside). COX-2 is expressed at higher levels in triple negative invasive breast cancers than in less aggressive ER-positive cancers (Gilhooly and Rose, 1999 Aug, Liu and Rose, 1996 Nov 15). COX-2 catalyzes the conversion of arachidonic acid into prostaglandin H2, a pro-inflammatory factor, and is therefore considered as a prognosis factor in breast cancer (Ristimäki et al., 2002 Feb 1, Parrett et al., 1997 Mar). Transfection with COX-2 triple negative MDA-MB-435 cells increased cell migration 2-fold compared to control cells in a transwell-Matrigel® assay. Antagonism of COX-2 through an inhibitor (NS-398) reversed this action in a dose-dependent way (Singh et al., 2005 May).
  • In vitro studies: Studies using cell lines have shown that exposure to inflammatory mediators can directly increase the invasive potential of cancer cells (Kumar). This can be assessed through assays measuring cell migration and invasion through ECM barriers in vitro.
  • Ex vivo studies: Studies using organotypic cultures or tissue explants have demonstrated that inflammatory stimuli can enhance the invasive properties of cells within their native tissue environment (Park). This provides a more realistic context compared to isolated cell lines. In vivo, the use of anti-inflammatory treatments such as celecoxib (COX-2 inhibitor) can reduce tumor growth and spread (Harris et al., 2000 Apr 15).
  • In vivo models: Studies in animal models, like mice, have shown that suppressing inflammation using drugs or genetic manipulations can lead to reduced tumor growth and invasion (Bakin). These models allow for investigation of the complex interplay between inflammation and invasion in a whole organism.
  • Clinical observations: Correlations between chronic inflammation and cancer risk: Although not directly demonstrating causality, epidemiological studies have observed associations between chronic inflammatory conditions and increased risk of certain cancers . This suggests a potential link between long-term inflammation and the development of invasive cancers (Schottenfeld). Epidemiologic evidence suggests that inflammatory breast cancers have the worse prognosis. Indeed, the median overall survival of patients with inflammatory breast cancer compared with those with non-inflammatory breast cancer tumors is 4.75 years versus 13.40 years for stage III disease and 2.27 years versus 3.40 years for stage IV disease (Schlichting et al., 2012 Aug, Fouad et al., 2017 Apr).
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
  • Causality vs. correlation: While epidemiological studies show associations between chronic inflammation and cancer risk, this doesn't necessarily prove causation. Other factors might contribute to both inflammation and cancer development, making it difficult to establish a direct cause-and-effect relationship (Schottenfeld)
  • Diverse roles of inflammation: Inflammation can play both pro-tumorigenic and anti-tumorigenic roles depending on the specific context and cell types involved (Mantovani). Acute inflammation can be beneficial for tissue repair, while chronic inflammation can promote cancer progression. Understanding the specific inflammatory response and its effects on different cells is crucial.
  • Heterogeneity of cancer and inflammation: Cancers are highly heterogeneous, meaning they can display diverse behaviors and responses to inflammation. Similarly, the specific types and duration of inflammatory responses can vary greatly. This makes it challenging to establish a universal link between all types of inflammation and all types of cancer invasion.
  •  Limitations of animal models: While animal models provide valuable insights, they may not always fully recapitulate the complexities of human cancer and inflammation (Mantovani). Additionally, ethical considerations limit the extent to which specific aspects of inflammation can be manipulated in humans for direct investigation.
  • Challenges in targeting inflammation for cancer therapy: Targeting the inflammatory microenvironment in cancer remains challenging. Broadly suppressing inflammation could have unintended consequences and potentially harm healthy tissues. Developing targeted therapies that specifically modulate specific aspects of the inflammatory response associated with increased invasion is an ongoing area of research (Alllavena).

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

Miller ME, Holloway AC, Foster WG. Benzo-[a]-pyrene increases invasion in MDA-MB-231 breast cancer cells via increased COX-II expression and prostaglandin E2 (PGE2) output. Clin Exp Metastasis. 2005;22(2):149–56.

57.       Belguise K, Guo S, Yang S, Rogers AE, Seldin DC, Sherr DH, et al. Green tea polyphenols reverse cooperation between c-Rel and CK2 that induces the aryl hydrocarbon receptor, slug, and an invasive phenotype. Cancer Res. 2007 Dec 15;67(24):11742–50.

58.       Pontillo CA, Rojas P, Chiappini F, Sequeira G, Cocca C, Crocci M, et al. Action of hexachlorobenzene on tumor growth and metastasis in different experimental models. Toxicol Appl Pharmacol. 2013 May 1;268(3):331–42.

59.       Yamashita N, Saito N, Zhao S, Terai K, Hiruta N, Park Y, et al. Heregulin-induced cell migration is promoted by aryl hydrocarbon receptor in HER2-overexpressing breast cancer cells. Exp Cell Res. 2018 May 1;366(1):34–40.

60.       Miret N, Zappia CD, Altamirano G, Pontillo C, Zárate L, Gómez A, et al. AhR ligands reactivate LINE-1 retrotransposon in triple-negative breast cancer cells MDA-MB-231 and non-tumorigenic mammary epithelial cells NMuMG. Biochem Pharmacol. 2020 May;175:113904.

61.       Degner SC, Papoutsis AJ, Selmin O, Romagnolo DF. Targeting of aryl hydrocarbon receptor-mediated activation of cyclooxygenase-2 expression by the indole-3-carbinol metabolite 3,3’-diindolylmethane in breast cancer cells. J Nutr. 2009 Jan;139(1):26–32.

62.       Vogel CFA, Li W, Wu D, Miller JK, Sweeney C, Lazennec G, et al. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch Biochem Biophys. 2011 Aug 1;512(1):78–86.

63.       Kolasa E, Houlbert N, Balaguer P, Fardel O. AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells. Chem Biol Interact. 2013 Apr 25;203(2):391–400.

64.       Vacher S, Castagnet P, Chemlali W, Lallemand F, Meseure D, Pocard M, et al. High AHR expression in breast tumors correlates with expression of genes from several signaling pathways namely inflammation and endogenous tryptophan metabolism. PloS One. 2018;13(1):e0190619.

65.       Malik D-E-S, David RM, Gooderham NJ. Interleukin-6 selectively induces drug metabolism to potentiate the genotoxicity of dietary carcinogens in mammary cells. Arch Toxicol. 2019 Oct;93(10):3005–20.

66.       Jönsson ME, Kubota A, Timme-Laragy AR, Woodin B, Stegeman JJ. Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. Toxicol Appl Pharmacol. 2012 Dec 1;265(2):166–74.

67.       Degner SC, Kemp MQ, Hockings JK, Romagnolo DF. Cyclooxygenase-2 promoter activation by the aromatic hydrocarbon receptor in breast cancer mcf-7 cells: repressive effects of conjugated linoleic acid. Nutr Cancer. 2007;59(2):248–57.

68.       Gilhooly EM, Rose DP. The association between a mutated ras gene and cyclooxygenase-2 expression in human breast cancer cell lines. Int J Oncol. 1999 Aug;15(2):267–70.

69.       Liu XH, Rose DP. Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res. 1996 Nov 15;56(22):5125–7.

70.       Ristimäki A, Sivula A, Lundin J, Lundin M, Salminen T, Haglund C, et al. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002 Feb 1;62(3):632–5.

71.       Parrett M, Harris R, Joarder F, Ross M, Clausen K, Robertson F. Cyclooxygenase-2 gene expression in human breast cancer. Int J Oncol. 1997 Mar;10(3):503–7.

72.       Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A. COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol. 2005 May;26(5):1393–9.

73.       Harris RE, Alshafie GA, Abou-Issa H, Seibert K. Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res. 2000 Apr 15;60(8):2101–3.

74.       Schlichting JA, Soliman AS, Schairer C, Schottenfeld D, Merajver SD. Inflammatory and non-inflammatory breast cancer survival by socioeconomic position in the Surveillance, Epidemiology, and End Results database, 1990-2008. Breast Cancer Res Treat. 2012 Aug;134(3):1257–68.

75.       Fouad TM, Barrera AMG, Reuben JM, Lucci A, Woodward WA, Stauder MC, et al. Inflammatory breast cancer: a proposed conceptual shift in the UICC-AJCC TNM staging system. Lancet Oncol. 2017 Apr;18(4):e228–32.

76.       Takahashi Y, Kawahara F, Noguchi M, Miwa K, Sato H, Seiki M, et al. Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2. FEBS Lett. 1999 Oct 22;460(1):145–8.

77.       Sivula A, Talvensaari-Mattila A, Lundin J, Joensuu H, Haglund C, Ristimäki A, et al. Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer. Breast Cancer Res Treat. 2005 Feb;89(3):215–20.

78.       Larkins TL, Nowell M, Singh S, Sanford GL. Inhibition of cyclooxygenase-2 decreases breast cancer cell motility, invasion and matrix metalloproteinase expression. BMC Cancer. 2006 Jul 10;6:181.

79.       Guyton DP, Evans DM, Sloan-Stakleff KD. Urokinase Plasminogen Activator Receptor (uPAR): A Potential Indicator of Invasion for In Situ Breast Cancer. Breast J. 2000 Mar;6(2):130–6.

Mantovani, A., et al. (2017). The yin-yang of inflammation in cancer. Immunity, 46(1), 16-22.

Mantovani, A., et al. (2019). Tumor-associated macrophages: potential targets for therapy. Trends in Immunology, 40(11), 740-752. https://pubmed.ncbi.nlm.nih.gov/31520593/

Allavena, P., et al. (2016. Novel therapeutic strategies to target the inflammatory microenvironment in cancer. Annals of Oncology, 27(8), iii1-iii10. https://pubmed.ncbi.nlm.nih.gov/27337594/

Karin, M., & Greten, F. R. (2005). ONCOGENE MODELS: NF-κB in inflammation and cancer. Science, 308(5721), 1086-1090.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646-674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446472/

Whiteside, T. L. (2009). The role of inflammation in cancer. Apoptosis, 14(6), 718-724. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704802/

Bakin, A. V., et al. (2000). Cyclooxygenase-2 expression in human esophageal cancer. The American Journal of Gastroenterology, 95(8), 2136-2141.

Soriano, A. H., et al. (2001). Celecoxib, a specific cyclooxygenase-2 inhibitor, in combination with FOLFOX-4 chemotherapy for advanced colorectal cancer. Journal of Clinical Oncology, 19(14), 3418-3425.

Condamine, T., et al. (2016). ELA-II pathway inhibition combined with platinum-based chemotherapy enhances survival in preclinical models of metastatic breast cancer. Cancer Immunology, Research, 4(2), 183-192. [https://pubmed.ncbi.nlm.nih.gov/26810606/]

Park, H. J., et al. (2010). IL-1β enhances the invasive potential of human oral epithelial cells through the activation of FAK and MMP-9. Journal of Dental Research, 89(8), 835-840.

Kumar, D., et al. (2010). NF-κB signaling in breast cancer: Potential targets for therapeutic intervention. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1805(2), 2489-2503. [https://pubmed.ncbi.nlm.nih.gov/20144685/]

Schottenfeld, D., & Beebe-Wood, L. (2012. Chronic inflammation and cancer prevention: A bird's-eye view. Nature Reviews Cancer, 12(3), 189-201. [https://pubmed.ncbi.nlm.nih.gov/22273994/]

Davidson, S., Coles, M., Thomas, T. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 21, 704–717 (2021). https://doi.org/10.1038/s41577-021-00540-z

Zhang T, Ma C, Zhang Z, Zhang H, Hu H. NF-κB signaling in inflammation and cancer. MedComm (2020). 2021 Dec 16;2(4):618-653. doi: 10.1002/mco2.104. PMID: 34977871; PMCID: PMC8706767.

Liu, T., Zhang, L., Joo, D. et al. NF-κB signaling in inflammation. Sig Transduct Target Ther 2, 17023 (2017). https://doi.org/10.1038/sigtrans.2017.23

López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009 Sep;1(6-7):303-14. doi: 10.1002/emmm.200900043. PMID: 20049734; PMCID: PMC3378143.

Suarez-Carmona M, Lesage J, Cataldo D, Gilles C. EMT and inflammation: inseparable actors of cancer progression. Mol Oncol. 2017 Jul;11(7):805-823. doi: 10.1002/1878-0261.12095. Epub 2017 Jun 26. PMID: 28599100; PMCID: PMC5496491.

Shaik-Dasthagirisaheb YB, Varvara G, Murmura G, Saggini A, Potalivo G, Caraffa A, Antinolfi P, Tete' S, Tripodi D, Conti F, Cianchetti E, Toniato E, Rosati M, Conti P, Speranza L, Pantalone A, Saggini R, Theoharides TC, Pandolfi F. Vascular endothelial growth factor (VEGF), mast cells and inflammation. Int J Immunopathol Pharmacol. 2013 Apr-Jun;26(2):327-35. doi: 10.1177/039463201302600206. PMID: 23755748.

Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12, 76 (2019). https://doi.org/10.1186/s13045-019-0760-3

Pan Y, Yu Y, Wang X, Zhang T. Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020 Dec 3;11:583084. doi: 10.3389/fimmu.2020.583084. Erratum in: Front Immunol. 2021 Dec 10;12:775758. PMID: 33365025; PMCID: PMC7751482.

Lee HS, Kim WJ. The Role of Matrix Metalloproteinase in Inflammation with a Focus on Infectious Diseases. Int J Mol Sci. 2022 Sep 11;23(18):10546. doi: 10.3390/ijms231810546. PMID: 36142454; PMCID: PMC9500641.

Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008 Feb;19(1):34-41. doi: 10.1016/j.semcdb.2007.07.003. Epub 2007 Jul 10. PMID: 17707664; PMCID: PMC2235912.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646-674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446472/

David-Stirn, N., et al. (2018). Stromalepithelial crosstalk in cancer progression. Nature Reviews Cancer, 18(3), 199-210. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855375/

Whiteside, T. L. (2009). The role of inflammation in cancer. Apoptosis, 14(6), 718-724. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704802/