Increase, Cytotoxicity (epithelial cells)

CL:0000066

CL epithelial cell

D010212

MESH papilloma

D002277

MESH Carcinoma

GO:0008219

GO cell death

GO:0006954

GO inflammatory response

GO:0008283

GO cell proliferation

MP:0005493

MP stomach epithelial hyperplasia

WIKI increased

Propylene oxide

2016-11-29T18:42:27

9606

NCBI Homo sapiens

10090

NCBI Mus musculus

10116

NCBI Rattus norvegicus

Increase, Cytotoxicity (epithelial cells)

Cellular

This key event is often associated with gavaged administration.

CL:0000066

CL epithelial cell

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:14

Increase, Inflammation

Cellular

Inflammation is complex to define.  Villeneuve et al. (2018) analyzed the varied biological responses, provided guidance to simplify the  process representing inflammation in adverse outcome pathways, and recommended 3 key steps: 1. Tissue resident cell activation 2. Increased Pro-inflammatory mediators 3. Leukocyte recruitment/activation.  Tissue resident cell activation generally occurs when healthy tissue is exposed to a stressor, or when damage occurs, initiating a signal response of pro-inflammatory mediators (ex. cytokines).  Pro-inflammatory mediators result in the production of lipids and proteins, signaling, and initiate leukocyte recruitment/activation.  Leukocyte recruitment/activation initiate inflammation and other morphological changes.  In cancer, inflammation is a cascade of events created by the host in response to the spread of the cancer (Coussens and Werb, 2002). In response to an injury or the presence of cancer, the host heals itself through inflammation. Indeed, the activation and the migration of  leukocytes (neutrophils, monocytes and eosinophils) to the wound induces the healing process. These inflammatory cells provide an extracellular matrix that forms upon which fibroblast and endothelial cells proliferate and migrate in order to recreate a normal environment. Damage to the epithelial layer initiate inflammatory reactions (Palmer et al. 2011).  In cancer, this inflammatory state induces cell proliferation, increases the production of reactive oxygen species leading to oxidative DNA damage, and reduces DNA repair (Coussens and Werb, 2002).  For review of inflammation caused by microplastics in mammals, see Wright and Kelly (2017).     Inflammation can be defined as the response of the organism to a tissue injury (Coussens). Indeed, in order to heal this injury, a multitude of chemical signals initiate and maintain a host response. Leukocytes (neutrophils, monocytes and eosinophils) are recruited to the site of the damage through the attraction by chemokines (TNF-α (tumour necrosis factor-α), interleukines…). A provisional extracellular matrix (ECM) is created, and fibroblast and endothelial cells proliferate and migrate to it. Wound healing is an example of physiological inflammation and is self-limiting (Coussens). In case of a dysregulation, inflammation can lead to pathologies. Inflammation can be caused by physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma (Singh). Inflammation was described as one of the hallmarks of cancer by Hannahan et al. as a response to tumor invasion through mainly two mechanisms: promoting genetic instatbility and supply pro-tumorogenic factors. First, inflammation in cancer promotes genetic instability (Mantovani, colotta). Macrophages, in contact with the inflammatory site can be responsible of a reactive stress oxygen reaction (ROS) (Maeda, Pollard, Grivennikov). Indeed, they generate high levels of reactive oxygen and nitrogen species which produce mutagenic agents (peroxynitrite), which in turn causes DNA mutations. Second, in inflammation, the tumor micro environment plays a critical role (Coussens). Indeed, in can supply growth factors, survival factors, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, and metastasis, and inductive signals that lead to activation of EMT and other hallmark-facilitating programs (Hannahan). For example, macrophages can become tumor associated macrophage which promote cell proliferation, angiogenesis, and invasion (Singh, Lin, Qian). Moreover, chronic inflammation can also lead to tumorigenesis (Karin, Singh). Indeed, since 1863, Virchow has hypothesized that chronic inflammation causes cell proliferation (Balkwill). According to Aggarwall, several pro-inflammatory markers such as TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX mediate suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis (Aggarwal).

Inflammation is generally detected in histopathological examination of organs (ex. liver, intestines) or in changes in gene expression (ex. interleukins).  Activation of the innate immune response and the release of various inflammatory cytokines can also be assessed (Flake and Morgan, 2017).   Several assays can be used to measure inflammation: <ul> <li style="text-align:justify">Histopathology on samples. Several scoring tools exist (Goeboes)</li> <li style="text-align:justify">Measuring chemokines in the blood (ELISA, multiplex bead assays : interleukines (IL1, IL6), TNF, interferon… ) (Brenner) and histopathology samples</li> <li style="text-align:justify">Measuring Prostaglandin levels, COX-2 (ELISA Liquid chromatography/tandem mass spectrometry, IHC)</li> <li style="text-align:justify">Transcription factors : STAT3 Activation, NF-κB Activation (ELISA RtPCR to measure mRNA</li> <li style="text-align:justify">Biomarkers (white cell count, CRP) ratios, and predictive score using </li> <li style="text-align:justify">Measuring ROS(DCFDA, horseradish peroxidase (HRP)-oxidizing substrates, SOD-inhibitable reduction of cytochrome c) (Murphy).</li> </ul>   Methods are extensively reviewed in Marchand et al and Murphy et al.

Taxonomic: appears to be present broadly, with representative studies focused on mammals (humans, lab mice, lab rats).   Extensive data exists on the presence of inflammation in human (Coussens, Aggarwal, Hannhan, Mantovani..) In human, many examples of chronic inflammation leading to cancer or cancer progression exist. For instance, Helicobacter pylori infection leads to gut cancer (Wang).

CL:0000255

CL eukaryotic cell

High Unspecific

High

All life stages

High High High

Flake, G.P., and Morgan, D.L. 2017. Pathology of diacetyl and 2,3-pentanedione airway lesions in a rat model of obliterative bronchiolitis. Toxicology, 388, 40–47. <a href="https://doi.org/10.1016/j.tox.2016.10.013">https://doi.org/10.1016/j.tox.2016.10.013</a> Palmer, S.M., Flake, G.P., Kelly, F.L., Zhang, H.L., Nugent, J.L., Kirby, P.J., Zhang, H.L., Nugent, J.L., Kirby, P.J., Foley, J.F., Gwinn, W.M., and Morgan, D.L. 2011. Severe airway epithelial injury, aberrant repair and Bronchiolitis obliterans develops after diacetyl instillation in rats. PLoS ONE, 6(3). <a href="https://doi.org/10.1371/journal.pone.0017644">https://doi.org/10.1371/journal.pone.0017644</a>   Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett. 2014 Apr 10;345(2):196-202. doi: 10.1016/j.canlet.2013.08.016. Epub 2013 Aug 24. PMID: 23981572. Naylor MS, Stamp GW, Foulkes WD, Eccles D, Balkwill FR. Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression. J Clin Invest. 1993;91:2194–206. Coussens L.M. and Werb Z. Inflammation and cancer. Nature. 2002 Dec 19-26;420(6917):860-7. doi: 10.1038/nature01322. PMID: 12490959; PMCID: PMC2803035. Wright, S.L. and Kelly, F.J.  2017.  Plastic and human health: a micro issue?  Enviromental Science and Technology 51: 6634-6647. Villeneuve, D.L., Landesmann, B., Allavena, P., Ashley, N., Bal-Price, A., Corsini, E., Halappanavar, S., Hussell, T., Laskin, D., Lawrence, T., Nikolic-Paterson, D., Pallary, M., Paini, A., Pietrs, R., Roth, R., and Tschudi-Monnet, F.  2018.  Toxicological Sciences 163(2): 346-352.     Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010 Apr 2;141(1):39-51. doi: 10.1016/j.cell.2010.03.014. PMID: 20371344; PMCID: PMC4994190. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013. PMID: 21376230. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: How hot is the link? Biochem Pharmacol. 2006;72:1605–21 Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019 Jul-Sep;18(3):121-126. doi: 10.4103/aam.aam_56_18. PMID: 31417011; PMCID: PMC6704802. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7 Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545 Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–44 Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability.  Maeda H, Akaike T. Nitric oxide and oxygen radicals in infection, inflammation, and cancer. Biochemistry (Mosc) 1998;63:854–65. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8 Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12, 76 (2019). <a href="https://doi.org/10.1186/s13045-019-0760-3" style="color:#467886; text-decoration:underline">https://doi.org/10.1186/s13045-019-0760-3</a> Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010 Mar 19;140(6):883-99. doi: 10.1016/j.cell.2010.01.025. PMID: 20303878; PMCID: PMC2866629.   Murphy, M.P., Bayir, H., Belousov, V. et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nat Metab 4, 651–662 (2022). <a href="https://doi.org/10.1038/s42255-022-00591-z" style="color:#467886; text-decoration:underline">https://doi.org/10.1038/s42255-022-00591-z</a> Geboes K, Riddell R, Öst A, et al A reproducible grading scale for histological assessment of inflammation in ulcerative colitis Gut 2000;47:404-409. Brenner DR, Scherer D, Muir K, Schildkraut J, Boffetta P, Spitz MR, Le Marchand L, Chan AT, Goode EL, Ulrich CM, Hung RJ. A review of the application of inflammatory biomarkers in epidemiologic cancer research. Cancer Epidemiol Biomarkers Prev. 2014 Sep;23(9):1729-51. doi: 10.1158/1055-9965.EPI-14-0064. Epub 2014 Jun 24. PMID: 24962838; PMCID: PMC4155060. AOPWiki 2016-11-29T18:41:23

2024-02-28T06:33:44

Increase, Regenerative cell proliferation (forestomach epithelial cells)

Cellular

UBERON:0008827

UBERON murine forestomach

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:14

Increase, Hyperplasia (forestomach epithelial cells)

Cellular

UBERON:0008827

UBERON murine forestomach

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:14

Increase, Papillomas/carcinomas (squamous cells)

Cellular

CL:0000076

CL squamous epithelial cell

AOPWiki 2016-11-29T18:41:27

2017-09-16T10:16:12

<upstream-id>68e45ccf-45ad-4970-810c-c696897383e7</upstream-id> <downstream-id>85cc8e5a-fab4-458a-add7-69050a09a7fb</downstream-id>

AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

<upstream-id>85cc8e5a-fab4-458a-add7-69050a09a7fb</upstream-id> <downstream-id>62539e78-f856-444a-bdb6-586818ff6a11</downstream-id>

AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

<upstream-id>62539e78-f856-444a-bdb6-586818ff6a11</upstream-id> <downstream-id>10077341-d9f2-412d-9a93-28c0f9e0cb07</downstream-id> Sustained regenerative cell proliferation directly leads to hyperplasia.

AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

<upstream-id>10077341-d9f2-412d-9a93-28c0f9e0cb07</upstream-id> <downstream-id>e04e9a49-9f18-4548-a7ba-2926dbd5cba4</downstream-id>

AOPWiki 2016-11-29T18:41:35

2016-12-03T16:38:00

Epithelial cytotoxicity leading to forestomach tumors (in mouse and rat)

Epithelial cytotoxicity- forestomach tumor

Charles Wood

Cancer AOP group. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

BY-SA

1.0

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

Not Specified

Not Specified adjacent

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Not Specified Male Not Specified Female Not Specified Not Specified

Proctor, D. M., Gatto, N. M., Hong, S. J., & Allamneni, K. P. (2007). Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment. Toxicol Sci, 98(2), 313-326. doi: 10.1093/toxsci/kfm075 AOPWiki 2016-11-29T18:41:16

2026-01-11T16:56:07