Aop: 298

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Chronic reactive oxygen species leading to human treatment-resistant gastric cancer

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Chronic ROS leading to human treatment-resistant gastric cancer

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Shihori Tanabe1), Sabina Quader2), Ryuichi Ono3), Horacio Cabral4), Kazuhiko Aoyagi5), Akihiko Hirose1), Hiroshi Yokozaki6), Hiroki Sasaki7), Ed Perkins8)

1Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

2Innovation Centre of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Japan

3Division of Cellular and Molecular Toxicology, Center for Biological Safety and Research, National Institute of Health Sciences, Japan

4Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Japan

5Department of Clinical Genomics, National Cancer Center Research Institute, Japan

6Department of Pathology, Kobe University of Graduate School of Medicine, Japan

7Department of Translational Oncology, National Cancer Center Research Institute, Japan

8Environmental Laboratory, US Army Engineer Research and Development Center, United States

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Shihori Tanabe   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Shihori Tanabe

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for comment. Do not cite EAGMST Under Review 1.58 Included in OECD Work Plan
This AOP was last modified on November 09, 2021 02:38

Revision dates for related pages

Page Revision Date/Time
Epithelial-mesenchymal transition May 13, 2021 01:37
Treatment-resistant gastric cancer May 13, 2021 02:10
Chronic reactive oxygen species November 09, 2021 00:35
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion May 13, 2021 22:29
Proliferation / beta-catenin activation May 13, 2021 01:36
Increases in cellular reactive oxygen species May 10, 2022 21:44
Chronic ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion May 13, 2021 02:22
Increases in cellular ROS leads to Sustained tissue damage, macrophage activation and Wnt secretion April 27, 2022 01:24
Sustained tissue damage, macrophage activation and Wnt secretion leads to Proliferation / beta-catenin activation November 09, 2021 01:23
Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition November 09, 2021 01:58
Epithelial-mesenchymal transition leads to Resistant gastric cancer May 13, 2021 03:08
Wnt May 29, 2019 03:59
WNT2 May 29, 2019 03:59
Porcupine January 19, 2020 21:19
Wntless January 19, 2020 21:20
Ionizing Radiation May 07, 2019 12:12
ferric nitrilotriacetate May 27, 2020 02:40

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The injury or sustained reactive oxygen species (ROS) causes resistance in human gastric cancer. This AOP entitled “Chronic reactive oxygen species leading to human treatment-resistant gastric cancer” consists of MIE (KE1753) as chronic ROS, followed by KE1 (KE1754) as sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion, KE2 (KE1755) as proliferation / beta-catenin activation, KE3 (KE1650) as epithelial-mesenchymal transition (EMT), and AO (KE1651) as human treatment-resistant gastric cancer. ROS has multiple roles such as development and progression of cancer, or apoptotic induction causing anti-tumor effects. In this AOP, we focus on the role of chronic ROS with sustained level to induce the therapy-resistance in human gastric cancer. EMT, which is cellular phenotypic change from epithelial to mesenchymal-like feature, demonstrates cancer stem cell-like characteristics in human gastric cancer. EMT is induced by Wnt/beta-catenin signaling, which confers rationale to have Wnt secretion and beta-catenin activation as KE1 and KE2 on the AOP, respectively.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1753 Chronic reactive oxygen species Chronic ROS
KE 1940 Increases in cellular reactive oxygen species Increases in cellular ROS
KE 1754 Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion Sustained tissue damage, macrophage activation and Wnt secretion
KE 1755 Proliferation / beta-catenin activation Proliferation / beta-catenin activation
KE 1650 Epithelial-mesenchymal transition Epithelial-mesenchymal transition
AO 1651 Treatment-resistant gastric cancer Resistant gastric cancer

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

1. Support for Biological Plausibility of KERs

MIE => KE1: Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Biological Plausibility of the MIE => KE1 is moderate.

Rationale: Sustained ROS increases caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling. Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion. ROS stimulate inflammatory factor production and Wnt/beta-catenin signaling (Vallée & Lecarpentier, 2018).

KE1 => KE2: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation

Biological Plausibility of the KE1 => KE2 is moderate.

Rationale: Secreted Wnt ligand stimulates Wnt/beta-catenin signaling, in which beta-catenin is activated. Wnt ligand binds to Frizzled receptor, which leads to GSK3beta inactivation. GSK3beta inactivation leads to beta-catenin dephosphorylation, which avoids the ubiquitination of the beta-catenin and stabilize the beta-catenin (Clevers & Nusse, 2012).

KE2 => KE3: Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)

Biological Plausibility of the KE2 => KE3 is moderate.

Rationale: Beta-catenin activation, of which mechanism include the stabilization of the dephosphorylated beta-catenin and translocation of beta-catenin into the nucleus, induces the formation of beta-catenin-TCF complex and transcription of transcription factors such as Snail, Zeb and Twist (Clevers & Nusse, 2012) (Ahmad et al., 2012; Pearlman, Montes de Oca, Pal, & Afaq, 2017; Sohn et al., 2019; W. Yang et al., 2019).

EMT-related transcription factors including Snail, ZEB and Twist are up-regulated in cancer cells (Diaz, Vinas-Castells, & Garcia de Herreros, 2014).  The transcription factors such as Snail, ZEB and Twist bind to E-cadherin (CDH1) promoter and inhibit the CDH1 transcription via the consensus E-boxes (5’-CACCTG-3’ or 5’-CAGGTG-3’), which leads to EMT (Diaz et al., 2014).

KE3 => AO: Epithelial-mesenchymal transition (EMT) leads to human treatment-resistant gastric cancer

Biological Plausibility of the KE3 => AO is moderate.

Rationale: Some population of the cells exhibiting EMT demonstrates the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).

EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). The increase in expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT are associated with therapy resistance (Smith & Bhowmick, 2016).  

2. Support for essentiality of KEs

KE1: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Essentiality of the KE1 is moderate.

Rationale for Essentiality of KEs in the AOP: The sustained tissue damage, macrophage activation and Wnt are essential for the subsequent beta-catenin activation and cancer resistance.

KE2: Proliferation / beta-catenin activation

Essentiality of the KE2 is moderate.

Rationale for Essentiality of KEs in the AOP:  Proliferation and beta-catenin activation are essential for the Wnt-induced cancer resistance.

KE3: Epithelial-mesenchymal transition (EMT)

Essentiality of the KE3 is moderate.

Rationale for Essentiality of KEs in the AOP: EMT is essential for the Wnt-induced cancer promotion and resistance to anti-cancer drug.

3. Empirical support for KERs

MIE => KE1: Chronic ROS leads to Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Empirical Support of the MIE => KE1 is moderate.

Rationale: Production of ROS by DNA double-strand break causes the tissue damages (Gao et al., 2019).

ROS signaling induces Wnt/beta-catenin signaling (Pérez et al., 2017).

KE1 => KE2: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion leads to Proliferation / beta-catenin activation

Empirical Support of the KE1 => KE2 is moderate.

Rationale: Sustained ROS increases caused by/causes DNA damage, which will alter several signaling pathways including Wnt signaling. Macrophages accumulate into injured tissue to recover the tissue damage, which may be followed by porcupine-induced Wnt secretion, which then activates beta-catenin leading to proliferation.

Wnt binds to FZD and activate the Wnt signaling (Clevers & Nusse, 2012; Janda, Waghray, Levin, Thomas, & Garcia, 2012; Nile et al., 2017). Wnt binding towards FZD induce the formation of the protein complex with LRP5/6 and DVL, leading to the down-stream signaling activation including beta-catenin (Clevers & Nusse, 2012).

KE2 => KE3: Proliferation / beta-catenin activation leads to Epithelial-mesenchymal transition (EMT)

Empirical Support of the KE2 => KE3 is moderate.

Rationale: Proliferation and beta-catenin activation induces the key transcription factors in EMT. Translocation of beta-catenin into the nucleus by Wnt/beta-catenin signaling pathway activation promotes EMT.

The inhibition of c-MET, which is overexpressed in diffuse-type gastric cancer, induced increase in phosphorylated beta-catenin, decrease in beta-catenin and Snail (Sohn et al., 2019).

The garcinol, which has an anti-cancer effect, increases phosphorylated beta-catenin, decreases beta-catenin and ZEB1/ZEB2, and inhibits EMT (Ahmad et al., 2012).

The inhibition of sortilin by AF38469 (a sortilin inhibitor) or small interference RNA (siRNA) results in a decrease in beta-catenin and Twist expression in human glioblastoma cells (W. Yang et al., 2019).

Histone deacetylase inhibitors affect EMT-related transcription factors including ZEB, Twist and Snail (Wawruszak et al., 2019).

Snail and Zeb induces EMT and suppress E-cadherin (CDH1) (Batlle et al., 2000; Diaz et al., 2014; Peinado, Olmeda, & Cano, 2007).

KE3 => AO: Epithelial-mesenchymal transition (EMT) leads to human treatment-resistant gastric cancer

Empirical Support of the KE3 => AO is moderate.

Rationale: EMT induces the expression of genes such as transporters of anti-cancer drug, which promotes anti-cancer drug resistance. EMT induces migration and metastasis of cancer cells, and share the phenotype of cancer stem cells, which is one of the hallmarks of human treatment-resistant gastric cancer (Tanabe et al., 2020a, 2020b).

EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in the resistance to doxorubicin (Saxena, Stephens, Pathak, & Rangarajan, 2011; Shibue & Weinberg, 2017).

TGFbeta-1 induced EMT results in the acquisition of cancer stem cell (CSC) like properties (Pirozzi et al., 2011; Shibue & Weinberg, 2017).

Snail-induced EMT induces cancer metastasis and resistance to dendritic cell-mediated immunotherapy (Kudo-Saito et al., 2009).

Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in the relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8+ T cell immunosuppression and metastasis (Chen et al., 2014).

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Homo sapiens

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Sustained ROS contributes into the initiation and development of human gastric cancer (Gu H. 2018).

Wnt signaling is involved in cancer malignancy (Tanabe, 2018).

Upon stimulation with Wnt ligand to Frizzled receptor, Wnt/beta-catenin signaling is activated. Wnt/beta-catenin consists of GSK3 beta inactivation, beta-catenin activation and up-regulation of transcription factors such as Zeb, Twist and Snail. The transcription factors Zeb, Twist and Snail relate to the activation of EMT-related genes. EMT is regulated with various gene networks (Tanabe, 2015c).

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

 The Wnt signaling promotes EMT and cancer malignancy in colorectal cancer (Lazarova & Bordonaro, 2017). Although the potential pathways other than Wnt signaling exist in EMT induction and the mechanism underlaid cancer malignancy, Wnt signaling is one of the main pathways to induce EMT and cancer malignancy (Polakis, 2012).

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Wnt signaling activates the CSCs to promote cancer malignancy (Reya & Clevers, 2005). The responses in KEs related to Wnt signaling, Frizzled activation, GSK3beta inactivation, beta-catenin activation, Snail, Zeb, Twist activation are dose-dependently related. The quantification of EMT and cancer malignancy would require the further investigation.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

AOP entitled “Chronic reactive oxygen species leading to human treatment-resistant gastric cancer” might be utilized for the development and risk assessment of anti-cancer drugs. EMT is involved in the acquisition of drug resistance, which is one of the critical features of cancer malignancy. The assessment of EMT would be the potential prediction of the adverse effects of anti-cancer drugs.

References

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

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