AOP-Wiki

AOP ID and Title:

AOP 298: Chronic reactive oxygen species leading to human treatment-resistant gastric cancer
Short Title: Chronic ROS leading to human treatment-resistant gastric cancer

Graphical Representation

Authors

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

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

Status

Author status OECD status OECD project SAAOP status
Open for comment. Do not cite EAGMST Under Review 1.58 Included in OECD Work Plan

Abstract

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.

Summary of the AOP

Events

Molecular Initiating Events (MIE), Key Events (KE), Adverse Outcomes (AO)

Sequence Type Event ID Title Short name
1 MIE 1753 Chronic reactive oxygen species Chronic ROS
2 KE 1754 Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion Sustained tissue damage, macrophage activation and Wnt secretion
3 KE 1755 Proliferation / beta-catenin activation Proliferation / beta-catenin activation
4 KE 1650 Epithelial-mesenchymal transition Epithelial-mesenchymal transition
5 AO 1651 Treatment-resistant gastric cancer Resistant gastric cancer

Key Event Relationships

Upstream Event Relationship Type Downstream Event Evidence Quantitative Understanding
Chronic reactive oxygen species adjacent Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion Moderate Moderate
Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion adjacent Proliferation / beta-catenin activation High Moderate
Proliferation / beta-catenin activation adjacent Epithelial-mesenchymal transition Moderate Moderate
Epithelial-mesenchymal transition adjacent Treatment-resistant gastric cancer High Moderate

Stressors

Name Evidence
Wnt High
WNT2 High
Porcupine Moderate
Wntless Moderate
Ionizing Radiation Moderate
ferric nitrilotriacetate Not Specified

Wnt

WNT induces EMT (J. Zhang, Tian, & Xing, 2016). 

WNT2

WNT2 induces EMT in cervical cancer (Zhou et al., 2016).

Porcupine

Porcupine palmitoleates Wnt and facilitates the secretion of the Wnt ligand (Yu & Virshup, 2014) .

Wntless

Wntless binds to and transport Wnt to the plasma membrane leading to the secretion of Wnt ligand (Yu & Virshup, 2014).

ferric nitrilotriacetate

Carcinogenic iron(III)-nitrilotriacetate induces reactive oxygen species production via trasfer of an electron to molecular oxygen to form reactive oxygen species [Tsuchiya K, Akai K, Tokumura A, Abe S, Tamaki T, Takiguchi Y, Fukuzawa K. Biochim Biophys Acta. 2005 Aug 30;1725(1):111-9. doi: 10.1016/j.bbagen.2005.05.001, Akai K, Tsuchiya K, Tokumura A, Kogure K, Ueno S, Shibata A, Tamaki T, Fukuzawa K. Free Radic Res. 2004 Sep;38(9):951-62. doi: 10.1080/1071576042000261945.].

 

Overall Assessment of the AOP

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 high.

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 high.

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 high.

Rationale: Dishevelled (DVL), a positive regulator of Wnt signaling, form the complex with FZD and lead to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang et al., 2015).

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: 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 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 the 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

Life Stage Applicability
Life Stage Evidence
All life stages High
Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens High NCBI
Sex Applicability
Sex Evidence
Unspecific High

Homo sapiens

Essentiality of the Key Events

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).

Weight of Evidence Summary

 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).

Quantitative Consideration

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)

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.

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Appendix 1

List of MIEs in this AOP

Event: 1753: Chronic reactive oxygen species

Short Name: Chronic ROS

Key Event Component

Process Object Action
response to reactive oxygen species reactive oxygen species increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:298 - Chronic reactive oxygen species leading to human treatment-resistant gastric cancer MolecularInitiatingEvent

Stressors

Name
Ionizing Radiation
ferric nitrilotriacetate
Arsenic

Biological Context

Level of Biological Organization
Molecular

Cell term

Cell term
cell

Organ term

Organ term
organ

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

Reactive oxygen species (ROS) are generated through NADPH oxidases consist of p47phox and p67phox. Arsenic produces ROS [Zhang et al., 2011].

Ionizing radiation induces ROS [Kruk et al., 2017].

Iron(III)-nitrilotriacetate induces reactive oxygen species production via the transfer of an electron to molecular oxygen to form ROS [Tsuchiya et al., 2005, Akai et al., 2004].

Ionizing Radiation

Ionizing radiation induces reactive oxygen species.

(Ref. Reactive Oxygen and Nitrogen Species in Carcinogenesis: Implications of Oxidative Stress on the Progression and Development of Several Cancer Types

Author(s): Joanna Kruk, Hassan Y. Aboul-Enein*. Journal Name: Mini-Reviews in Medicinal Chemistry,

Volume 17 , Issue 11 , 2017, DOI : 10.2174/1389557517666170228115324)

ferric nitrilotriacetate

Iron(III)-nitrilotriacetate induces reactive oxygen species production via trasfer of an electron to molecular oxygen to form reactive oxygen species [Tsuchiya K, Akai K, Tokumura A, Abe S, Tamaki T, Takiguchi Y, Fukuzawa K. Biochim Biophys Acta. 2005 Aug 30;1725(1):111-9. doi: 10.1016/j.bbagen.2005.05.001, Akai K, Tsuchiya K, Tokumura A, Kogure K, Ueno S, Shibata A, Tamaki T, Fukuzawa K. Free Radic Res. 2004 Sep;38(9):951-62. doi: 10.1080/1071576042000261945.]

 

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens Moderate NCBI
Life Stage Applicability
Life Stage Evidence
All life stages Moderate
Sex Applicability
Sex Evidence
Unspecific High

Reactive oxygen species (ROS) are increased in human gastric cancer (Homo sapiens) [Gu et al., 2018].

Key Event Description

Reactive oxygen species (ROS) are radicals, ions, or molecules that have a single unpaired electron in their outermost shell of electrons, which can be categorized into two groups: free oxygen radicals and non-radical ROS [Liou et al., 2010]. Free oxygen radicals include superoxide (O2·-), hydroxyl radical (·OH), nitric oxide (NO·), organic radicals (R·), peroxyl radicals (ROO·), alkoxyl radicals (RO·), thiyl radicals (RS·), sulfonyl radicals (ROS·), thiyl peroxyl radicals (RSOO·), and disulfides (RSSR). Non-radical ROS include hydrogen peroxide (H2O2), singlet oxygen (1O2), ozone/trioxygen (O3), organic hydroperoxides (ROOH), hypochloride (HOCl), peroxynitrite (ONO-), nitrosoperoxycarbonate anion (O=NOOCO2-), nitrocarbonate anion (O2NOCO2-), dinitrogen dioxide (N2O2), nitronium (NO2+), and highly reactive lipid- or carbohydrate-derived carbonyl compounds [Liou et al., 2010].

ROS are generated through NADPH oxidases consists of p47phox and p67phox. Arsenic produces ROS [Zhang et al., 2011]. The primary site of action for this event is DNA or proteins etc.

ROS play an important role in tumorigenesis [Zhang et al., 2011].

Chronic low-level increased ROS can alter the tumor microenvironment and promote cancer stem cell renewal, leading to therapeutic resistance [Gu et al., 2018].

The reason why this chronic ROS KE has been created is because it is important to have chronic ROS, but not just instant increased ROS, since ROS have a double-edged effect.  

How it is Measured or Detected

Hydroxyl, peroxyl, or other ROS can be measured using a fluorescence probe, 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA), at fluorescence detection at 480 nm/530 nm.

Hydrogen peroxide (H2O2) can be detected with a colorimetric probe, which reacts with H2O2 in a 1:1 stoichiometry to produce a bright pink colored product, followed by the detection with a standard colorimetric microplate reader with a filter in the 540-570 nm range.

ROS in blood can be detected using superparamagnetic iron oxide nanoparticles (SPION)-based biosensor [Lee et al., 2020].

ROS can be detected by fluorescent probes such as p-methoxy-phenol derivative [Ashoka et al., 2020].

References

Akai K, Tsuchiya K, Tokumura A, Kogure K, Ueno S, Shibata A, Tamaki T, Fukuzawa K. Free Radic Res. 2004 Sep;38(9):951-62. doi: 10.1080/1071576042000261945

Ashoka, A. H., Ali, F., Tiwari, R., Kumari, R., Pramanik, S. K., & Das, A. (2020). Recent Advances in Fluorescent Probes for Detection of HOCl and HNO. ACS omega, 5(4), 1730-1742. doi:10.1021/acsomega.9b03420

Gu, H., Huang, T., Shen, Y., Liu, Y., Zhou, F., Jin, Y., . . . Wei, Y. (2018). Reactive Oxygen Species-Mediated Tumor Microenvironment Transformation: The Mechanism of Radioresistant Gastric Cancer. Oxidative medicine and cellular longevity, 2018, 5801209-5801209. doi:10.1155/2018/5801209

Kruk J, Aboul-Enein H. Y. (2017). Reactive Oxygen and Nitrogen Species in Carcinogenesis: Implications of Oxidative Stress on the Progression and Development of Several Cancer TypesJournal Name: Mini-Reviews in Medicinal Chemistry, 17:11. doi:10.2174/1389557517666170228115324)

Lee, D. Y., Kang, S., Lee, Y., Kim, J. Y., Yoo, D., Jung, W., . . . Jon, S. (2020). PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood. Theranostics, 10(5), 1997-2007. doi:10.7150/thno.39662

Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010 May;44(5):479-96. doi:10.3109/10715761003667554. PMID: 20370557; PMCID: PMC3880197.

Tsuchiya K, Akai K, Tokumura A, Abe S, Tamaki T, Takiguchi Y, Fukuzawa K. Biochim Biophys Acta. 2005 Aug 30;1725(1):111-9. doi:10.1016/j.bbagen.2005.05.001

Zhang, Z., Wang, X., Cheng, S., Sun, L., Son, Y.-O., Yao, H., . . . Shi, X. (2011). Reactive oxygen species mediate arsenic induced cell transformation and tumorigenesis through Wnt/β-catenin pathway in human colorectal adenocarcinoma DLD1 cells. Toxicology and Applied Pharmacology, 256(2), 114-121. doi:10.1016/j.taap.2011.07.016

 

List of Key Events in the AOP

Event: 1754: Sustained tissue damage / macrophage activation / porcupine-induced Wnt secretion

Short Name: Sustained tissue damage, macrophage activation and Wnt secretion

Key Event Component

Process Object Action
Wnt protein secretion protein-serine O-palmitoleoyltransferase porcupine increased

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:298 - Chronic reactive oxygen species leading to human treatment-resistant gastric cancer KeyEvent

Stressors

Name
Radiation

Biological Context

Level of Biological Organization
Tissue

Organ term

Organ term
organ

Evidence for Perturbation by Stressor

Radiation

Radiation induces porcupine-induced Wnt secretion in macrophage (Saha et al., 2016a).

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Life Stage Applicability
Life Stage Evidence
All life stages Moderate
Sex Applicability
Sex Evidence
Unspecific High

Oligomerization of FZD and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) activates Wnt/beta-catenin signaling in Homo sapiens (Hua et al., 2018).

Key Event Description

Porcupine, which is a trans-membrane endoplasmic reticulum O-acyl transferase, is important for the secretion of Wnt ligands(Saha et al., 2016a). WNTs are secreted proteins that contain 22-24 conserved cysteine residues (Foulquier et al., 2018). The WNT molecules consist of molecular families including WNT1, WNT2, WNT2B/WNT13, WNT3, WNT4, WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A, WNT8B, WNT10B, WNT11, and WNT16. (Clevers & Nusse, 2012; M. Katoh, 2001; Kusserow et al., 2005)

Wnt proteins consist of 350-400 amino acids (Saito-Diaz et al., 2013).

WNT ligands are known to trigger at least three different downstream signaling cascades including canonical WNT/beta-catenin signaling pathway, non-canonical WNT/Ca2+ pathway, and planer cell polarity (PCP) pathway(De, 2011; Lai, Chien, & Moon, 2009; Willert & Nusse, 2012). WNTs bind to Frizzled proteins, which are seven-pass transmembrane receptors with an extracellular N-terminal cysteine-rich domain (Bhanot et al., 1996; Clevers, 2006). Wnt signaling begins with the binding of Wnt ligand towards the Frizzled receptors (Mohammed et al., 2016).

Wnt ligands bind to Frizzled (FZD) receptors which are seven transmembrane-domain protein receptors (Nile, Mukund, Stanger, Wang, & Hannoush, 2017). At least 10 FZD receptors are identified in human cells. FZD receptor is activated by Wnt ligand binding (MacDonald, Tamai, & He, 2009). 

How it is Measured or Detected

  • Secretion of WNT requires a number of other dedicated factors including the sortin receptor Wntless (WLS), which binds to Wnt and escorts it to the cell surface (Banziger et al., 2006; Ching & Nusse, 2006)
  • Wnt signaling is activated by the gene mutations of the signaling components (Ziv et al., 2017).
  • Wnt1, Wnt3a, and Wnt5a protein expression are measured by immunoblotting using antibodies for Wnt1, Wnt3a, and Wnt5a, respectively (J. Du et al., 2016; B. Wang et al., 2017).
  • WNT2, of which expression is detected by quantitative PCR, immunoblotting, and immunohistochemistry, induces EMT (Zhou et al., 2016).
  • Frizzled receptor protein level on the cell surface is measured by flow cytometry with pan-FZD antibody (Jiang et al., 2015; Zeng et al., 2018). DVL protein level is measured by immunoblotting with anti-DVL2 antibodies (Zeng et al., 2018).
  • Fzd mRNA level is measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (Zeng et al., 2018).
  • The up-regulation of WNT ligand expression occurs in Homo sapiens (B. Wang et al., 2017).
  • The Wnt genes play an important role in the secretion from cells, glycosylation, and tight association with the cell surface and extracellular matrix in Drosophila melanogaster (Willert & Nusse, 2012).

References

Banziger, C., Soldini, D., Schutt, C., Zipperlen, P., Hausmann, G., & Basler, K. (2006). Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell, 125(3), 509-522. doi:10.1016/j.cell.2006.02.049

Bhanot, P., Brink, M., Samos, C. H., Hsieh, J.-C., Wang, Y., Macke, J. P., . . . Nusse, R. (1996). A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature, 382, 225. doi:10.1038/382225a0

Ching, W., & Nusse, R. (2006). A dedicated Wnt secretion factor. Cell, 125(3), 432-433. doi:10.1016/j.cell.2006.04.018

Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127(3), 469-480. doi:10.1016/j.cell.2006.10.018

Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. doi:10.1016/j.cell.2012.05.012

De, A. (2011). Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin (Shanghai), 43(10), 745-756. doi:10.1093/abbs/gmr079

Du, J., Zu, Y., Li, J., Du, S., Xu, Y., Zhang, L., . . . Yang, C. (2016). Extracellular matrix stiffness dictates Wnt expression through integrin pathway. Sci Rep, 6, 20395. doi:10.1038/srep20395

Foulquier, S., Daskalopoulos, E. P., Lluri, G., Hermans, K. C. M., Deb, A., & Blankesteijn, W. M. (2018). WNT Signaling in Cardiac and Vascular Disease. Pharmacol Rev, 70(1), 68-141. doi:10.1124/pr.117.013896

Hua, Y., Yang, Y., Li, Q., He, X., Zhu, W., Wang, J., & Gan, X. (2018). Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/beta-catenin pathway. J Biol Chem, 293(51), 19710-19724. doi:10.1074/jbc.RA118.004434

Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell, 58(3), 522-533. doi:10.1016/j.molcel.2015.03.015

Katoh, M. (2001). Molecular cloning and characterization of human WNT3. International journal of oncology, 19(5), 977-982. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11604997

Kusserow, A., Pang, K., Sturm, C., Hrouda, M., Lentfer, J., Schmidt, H. A., . . . Holstein, T. W. (2005). Unexpected complexity of the Wnt gene family in a sea anemone. Nature, 433(7022), 156-160. doi:10.1038/nature03158

Lai, S. L., Chien, A. J., & Moon, R. T. (2009). Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res, 19(5), 532-545. doi:10.1038/cr.2009.41

MacDonald, B. T., Tamai, K., & He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell, 17(1), 9-26. doi:10.1016/j.devcel.2009.06.016

Mohammed, M. K., Shao, C., Wang, J., Wei, Q., Wang, X., Collier, Z., . . . Lee, M. J. (2016). Wnt/beta-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis, 3(1), 11-40. doi:10.1016/j.gendis.2015.12.004

Nile, A. H., Mukund, S., Stanger, K., Wang, W., & Hannoush, R. N. (2017). Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci U S A, 114(16), 4147-4152. doi:10.1073/pnas.1618293114

Saha, S., Aranda, E., Hayakawa, Y., Bhanja, P., Atay, S., Brodin, N. P., . . . Pollard, J. W. (2016). Macrophage-derived extracellular vesicle-packaged WNTs rescue intestinal stem cells and enhance survival after radiation injury. Nature Communications, 7(1), 13096. doi:10.1038/ncomms13096

Saito-Diaz, K., Chen, T. W., Wang, X., Thorne, C. A., Wallace, H. A., Page-McCaw, A., & Lee, E. (2013). The way Wnt works: components and mechanism. Growth Factors, 31(1), 1-31. doi:10.3109/08977194.2012.752737

Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). doi:10.1042/BSR20171092

Willert, K., & Nusse, R. (2012). Wnt proteins. Cold Spring Harb Perspect Biol, 4(9), a007864. doi:10.1101/cshperspect.a007864

Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. Proc Natl Acad Sci U S A, 115(44), E10362-E10369. doi:10.1073/pnas.1808575115

Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. doi:10.1371/journal.pone.0160414

Ziv, E., Yarmohammadi, H., Boas, F. E., Petre, E. N., Brown, K. T., Solomon, S. B., . . . Erinjeri, J. P. (2017). Gene Signature Associated with Upregulation of the Wnt/beta-Catenin Signaling Pathway Predicts Tumor Response to Transarterial Embolization. J Vasc Interv Radiol, 28(3), 349-355 e341. doi:10.1016/j.jvir.2016.11.004

Event: 1755: Proliferation / beta-catenin activation

Short Name: Proliferation / beta-catenin activation

Key Event Component

Process Object Action
regulation of beta-catenin-TCF complex assembly beta-catenin-TCF complex occurrence

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:298 - Chronic reactive oxygen species leading to human treatment-resistant gastric cancer KeyEvent

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
cell

Organ term

Organ term
organ

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens High NCBI
Life Stage Applicability
Life Stage Evidence
All life stages Moderate
Sex Applicability
Sex Evidence
Unspecific High

Beta-catenin is stabilized and translocated into nucleus in Homo sapiens (Huang et al., 2019).

Beta-catenin is activated in Homo sapiens (Huang et al., 2019) (Naujok et al., 2014).

Key Event Description

Upon the Wnt signaling activation, beta-catenin is stabilized and activated via inhibition of the phosphorylation by GSK3beta (Huang et al., 2019). Once the beta-catenin is stabilized, it translocates into the nucleus and enhances the expression of target genes of Wnt/beta-catenin signaling pathway (Huang et al., 2019). Beta-catenin activation is related to cancer (Tanabe, 2014).

Dishevelled (DVL), a positive regulator of Wnt signaling, forms the complex with FZD and leads to trigger the Wnt signaling together with Wnt coreceptor low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) (Clevers & Nusse, 2012; Jiang, et al., 2015). DVL, however, has a controversial role to promote Wnt receptor degradation (Jiang et al., 2015). Meanwhile, DVL-dependent regulation of FZD level is involved in mTORC1 signaling suppression via Wnt/beta-catenin signaling (Zeng et al., 2018). The recruitment of Axin to the DVL-FZD complex induces the beta-catenin stabilization and activation. The stabilized beta-catenin translocates into the nucleus, which forms the complex with TCF to induce the up-regulated expression of proliferation-related genes.

How it is Measured or Detected

The beta-catenin level in nucleus is measured by immunoblotting with anti-beta-catenin antibody (Huang et al., 2019).

The beta-catenin nuclear translocation is measured by immunofluorescence assay (Huang et al., 2019).

Activity of beta-catenin is measured by Wnt/beta-catenin activity assay, in which the vector containing the firefly luciferase gene controlled by TCF/LEF binding sites is transfected in the cells (Naujok et al., 2014).

References

Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192-1205. doi:10.1016/j.cell.2012.05.012

Huang, J. Q., Wei, F. K., Xu, X. L., Ye, S. X., Song, J. W., Ding, P. K., . . . Gong, L. Y. (2019). SOX9 drives the epithelial-mesenchymal transition in non-small-cell lung cancer through the Wnt/beta-catenin pathway. J Transl Med, 17(1), 143. doi:10.1186/s12967-019-1895-2

Jiang, X., Charlat, O., Zamponi, R., Yang, Y., & Cong, F. (2015). Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Mol Cell, 58(3), 522-533. doi:10.1016/j.molcel.2015.03.015

Naujok, O., Lentes, J., Diekmann, U., Davenport, C., & Lenzen, S. (2014). Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. BMC Res Notes, 7, 273. doi:10.1186/1756-0500-7-273

Tanabe, S. (2014). Role of mesenchymal stem cells in cell life and their signaling. World journal of stem cells, 6(1), 24-32. doi:10.4252/wjsc.v6.i1.24

Zeng, H., Lu, B., Zamponi, R., Yang, Z., Wetzel, K., Loureiro, J., . . . Cong, F. (2018). mTORC1 signaling suppresses Wnt/beta-catenin signaling through DVL-dependent regulation of Wnt receptor FZD level. Proc Natl Acad Sci U S A, 115(44), E10362-E10369. doi:10.1073/pnas.1808575115

Event: 1650: Epithelial-mesenchymal transition

Short Name: Epithelial-mesenchymal transition

Key Event Component

Process Object Action
epithelial to mesenchymal transition cellular_component occurrence

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:298 - Chronic reactive oxygen species leading to human treatment-resistant gastric cancer KeyEvent

Stressors

Name
GOLPH3
LiCl
D-2-hydroxyglutarate

Biological Context

Level of Biological Organization
Cellular

Cell term

Cell term
cell

Organ term

Organ term
organ

Evidence for Perturbation by Stressor

GOLPH3

GOLPH3 induces EMT (Sun et al., 2017).

LiCl

LiCl induces EMT (Fang et al., 2018).

D-2-hydroxyglutarate

D-2-hydroxyglutarate induces EMT (Colvin et al., 2016).

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens High NCBI
Life Stage Applicability
Life Stage Evidence
All life stages High
Sex Applicability
Sex Evidence
Unspecific High
  • Wnt5a expression leads to epithelial-mesenchymal transition (EMT) and metastasis in non-small-cell lung cancer in Homo sapiens (Wang et al., 2017).
  • WNT2 expression lead to EMT induction in Homo sapiens (Zhou et al., 2016).
  • EMT is induced in cancer and involved in cancer metastasis in Homo sapiens (Suarez-Carmona, Lesage, Cataldo, & Gilles, 2017) (Du & Shim, 2016).

Key Event Description

Epithelial-mesenchymal transition (EMT) is a phenomenon in which the cells transit from epithelial-like into mesenchymal-like phenotypes (S. Tanabe, 2017; Shihori Tanabe, Komatsu, Kazuhiko, Yokozaki, & Sasaki, 2015). In cancer, cells exhibiting EMT features contribute into the metastasis and drug resistance.

It is known that D-2-hydroxyglurate induces EMT(Guerra et al., 2017; Jia, Park, Jung, Levine, & Kaipparettu, 2018; Mishra et al., 2018; Sciacovelli & Frezza, 2017). D-2-hydroxyglurate, an inhibitor of Jumonji-family histone demethylase, increased the trimethylation of histone H3 lysine 4 (H3K4) in the promoter region of the ZEB1, followed by the induction of EMT (Colvin et al., 2016).

Wnt5a induces EMT and metastasis in non-small-cell lung cancer (Wang, Tang, Gong, Zhu, & Liu, 2017).

EMT is related to Wnt/beta-catenin signaling and important for cancer (S. Tanabe, Kawabata, Aoyagi, Yokozaki, & Sasaki, 2016)

TGFbeta induces EMT (Wendt, Smith, & Schiemann, 2010).

ZEB is one of the important transcription factors for EMT regulation (Zhang, Sun, & Ma, 2015).

SNAI1 (Snail) is an important transcription factor for cell differentiation and survival, and the phosphorylation and nuclear localization of Snail1 induced by Wnt signaling pathways are critical for the regulation of EMT (Kaufhold & Bonavida, 2014).

Transcription factors SNAI1 and TWIST1 induce EMT (Hodge, Cui, Gamble, & Guo, 2018) (Mani et al., 2008)

It is suggested that Sp1, a transcription factor involved in cell growth and metastasis, is induced by cytochrome P450 1B1 (CYP1B1), and promotes EMT, which leads to cell proliferation and metastasis (Kwon et al., 2016).

How it is Measured or Detected

  • EMT can be detected by immunostaining with pro-surfactant protein-C (pro-SPC) and N-cadherin in idiopathic pulmonary fibrosis (IPF) lung in vivo (Kim et al., 2006).
  • TGFbeta induces EMT, which can be detected by immunostaining with vimentin in lung aloevela in vivo (Kim et al., 2006).

References

Colvin, H., Nishida, N., Konno, M., Haraguchi, N., Takahashi, H., Nishimura, J., . . . Ishii, H. (2016). Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial-Mesenchymal Transition and is Associated with Distant Metastasis in Colorectal Cancer. Sci Rep, 6, 36289. doi:10.1038/srep36289

Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965

Fang, C. X., Ma, C. M., Jiang, L., Wang, X. M., Zhang, N., Ma, J. N., . . . Zhao, Y. D. (2018). p38 MAPK is Crucial for Wnt1- and LiCl-Induced Epithelial Mesenchymal Transition. Curr Med Sci, 38(3), 473-481. doi:10.1007/s11596-018-1903-4

Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. Front Oncol, 7, 295. doi:10.3389/fonc.2017.00295

Hodge, D. Q., Cui, J., Gamble, M. J., & Guo, W. (2018). Histone Variant MacroH2A1 Plays an Isoform-Specific Role in Suppressing Epithelial-Mesenchymal Transition. Sci Rep, 8(1), 841. doi:10.1038/s41598-018-19364-4

Jia, D., Park, J. H., Jung, K. H., Levine, H., & Kaipparettu, B. A. (2018). Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells, 7(3). doi:10.3390/cells7030021

Kaufhold, S., & Bonavida, B. (2014). Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention. J Exp Clin Cancer Res, 33, 62. doi:10.1186/s13046-014-0062-0

Kim, K. K., Kugler, M. C., Wolters, P. J., Robillard, L., Galvez, M. G., Brumwell, A. N., . . . Chapman, H. A. (2006). Alveolar epithelial cell mesenchymal transition develops <em>in vivo</em> during pulmonary fibrosis and is regulated by the extracellular matrix. Proceedings of the National Academy of Sciences, 103(35), 13180. doi:10.1073/pnas.0605669103

Kwon, Y. J., Baek, H. S., Ye, D. J., Shin, S., Kim, D., & Chun, Y. J. (2016). CYP1B1 Enhances Cell Proliferation and Metastasis through Induction of EMT and Activation of Wnt/beta-Catenin Signaling via Sp1 Upregulation. PLoS One, 11(3), e0151598. doi:10.1371/journal.pone.0151598

Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., . . . Weinberg, R. A. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704-715. doi:10.1016/j.cell.2008.03.027

Mishra, P., Tang, W., Putluri, V., Dorsey, T. H., Jin, F., Wang, F., . . . Ambs, S. (2018). ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming. J Clin Invest, 128(1), 323-340. doi:10.1172/JCI93815

Sciacovelli, M., & Frezza, C. (2017). Metabolic reprogramming and epithelial-to-mesenchymal transition in cancer. FEBS J, 284(19), 3132-3144. doi:10.1111/febs.14090

Suarez-Carmona, M., Lesage, J., Cataldo, D., & Gilles, C. (2017). EMT and inflammation: inseparable actors of cancer progression. Mol Oncol, 11(7), 805-823. doi:10.1002/1878-0261.12095

Sun, J., Yang, X., Zhang, R., Liu, S., Gan, X., Xi, X., . . . Sun, Y. (2017). GOLPH3 induces epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in epithelial ovarian cancer. Cancer Med, 6(4), 834-844. doi:10.1002/cam4.1040

Tanabe, S. (2017). Molecular markers and networks for cancer and stem cells. J Embryol Stem Cell Res, 1(1).

Tanabe, S., Kawabata, T., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Gene expression and pathway analysis of CTNNB1 in cancer and stem cells. World J Stem Cells, 8(11), 384-395. doi:10.4252/wjsc.v8.i11.384

Tanabe, S., Komatsu, M., Kazuhiko, A., Yokozaki, H., & Sasaki, H. (2015). Implications of epithelial-mesenchymal transition in gastric cancer. Translational Gastrointestinal Cancer, 4(4), 258-264. Retrieved from http://tgc.amegroups.com/article/view/6996

Wang, B., Tang, Z., Gong, H., Zhu, L., & Liu, X. (2017). Wnt5a promotes epithelial-to-mesenchymal transition and metastasis in non-small-cell lung cancer. Biosci Rep, 37(6). doi:10.1042/BSR20171092

Wendt, M. K., Smith, J. A., & Schiemann, W. P. (2010). Transforming growth factor-beta-induced epithelial-mesenchymal transition facilitates epidermal growth factor-dependent breast cancer progression. Oncogene, 29(49), 6485-6498. doi:10.1038/onc.2010.377

Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle, 14(4), 481-487. doi:10.1080/15384101.2015.1006048

Zhou, Y., Huang, Y., Cao, X., Xu, J., Zhang, L., Wang, J., . . . Zheng, M. (2016). WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial-Mesenchymal Transition. PLoS One, 11(8), e0160414. doi:10.1371/journal.pone.0160414

List of Adverse Outcomes in this AOP

Event: 1651: Treatment-resistant gastric cancer

Short Name: Resistant gastric cancer

Key Event Component

Process Object Action
regulation of cellular response to drug occurrence

AOPs Including This Key Event

AOP ID and Name Event Type
Aop:298 - Chronic reactive oxygen species leading to human treatment-resistant gastric cancer AdverseOutcome

Biological Context

Level of Biological Organization
Tissue

Organ term

Organ term
organ

Domain of Applicability

Taxonomic Applicability
Term Scientific Term Evidence Links
Homo sapiens Homo sapiens High NCBI
Life Stage Applicability
Life Stage Evidence
All life stages High
Sex Applicability
Sex Evidence
Unspecific High

Drug resistance occurs in Homo sapiens (Du & Shim, 2016).

Key Event Description

It is known that diffuse-type gastric cancer, which has a poor prognosis, is treatment-resistant and more malignant compared to intestinal-type gastric cancer (Tanabe, Aoyagi, Yokozaki, & Sasaki, 2014). Drug resistance is involved in EMT, which is an important phenomenon exhibiting the feature similar to cancer stem cells (CSCs) (Du & Shim, 2016).

EMT is involved in metastasis and cancer therapy resistance (Smith & Bhowmick, 2016).

How it is Measured or Detected

Treatment-resistant gastric cancer and EMT can be detected with biomarkers (Zeisberg & Neilson, 2009).

Treatment-resistant gastric cancer which exhibits EMT phenotype can be detected as the increase level of the transcription factors, Zeb, Twist and Snail, related to the activation of EMT-related genes.

Regulatory Significance of the AO

Drug resistance is very important in cancer treatment since cancer metastasis and recurrence are some of the main obstacles to treat cancer. Cancer stem cells that share the phenotype of EMT  may be targeted in the anti-cancer drug development. 

References

Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965

Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in Metastasis and Therapy Resistance. J Clin Med, 5(2). doi:10.3390/jcm5020017

Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2014). Gene expression signatures for identifying diffuse-type gastric cancer associated with epithelial-mesenchymal transition. International journal of oncology, 44(6), 1955-1970. doi:10.3892/ijo.2014.2387

Tanabe S, Quader S, Cabral H, Ono R. Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. Front Pharmacol, 2020;11:904.

Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, et al. Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer. Cancers (Basel), 2020;12(12).

Zeisberg, M., & Neilson, E. G. (2009). Biomarkers for epithelial-mesenchymal transitions. J Clin Invest, 119(6), 1429-1437. doi:10.1172/JCI36183

Appendix 2

List of Key Event Relationships in the AOP