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Event: 1651

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Treatment-resistant gastric cancer

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Resistant gastric cancer

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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 et al., 2014). Drug resistance is involved in EMT, which is an important phenomenon exhibiting features 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

In the context of the EMOD/M2AOP prototyping, there are 2 components to the How it is Measured or Detected field, a structured component for adding Assay information and a free text component for unstructured descriptive information.In the free text field, include a description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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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 increased level of the transcription factors, zinc finger E-box-binding homeobox 1/2 (ZEB1/2), SNAI1/2, and TWIST2 which are associated with the activation of EMT-related genes (Tanabe et al., 2022a and 2022b).

Observations 2.0

Observed meausures are instances of assay results that support this Key Event More help

ID	Experimental Effect	Biological Object	Biological Process	Method of Measurement	Notes	Evidence Source ID	Citation (first author, year)

Observed Measures 1.0

Observed meausures are instances of assay results that support this Key Event More help

ID	Stressor	Sample (short_name)	Assay	Effect

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
regulation of cellular response to drug		occurrence

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
organ

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Increases in ROS and chronic ROS leading to human treatment-resistant gastric cancer	AdverseOutcome	Agnes Aggy (send email)	Open for comment. Do not cite	EAGMST 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 KE.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 in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Evidence Supporting the Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

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

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

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

References

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

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. (2020a). Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. Front Pharmacol, 11, 904. doi:10.3389/fphar.2020.00904

Tanabe S, Quader S, Ono R, Cabral H, Aoyagi K, Hirose A, Yokozaki H., Sasaki, H. (2020b). Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer. Cancers (Basel), 12(12), 3833. doi:10.3390/cancers12123833

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