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Event: 1982

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

metastatic breast 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. The short name should be less than 80 characters in length. More help
Metastasis, Breast Cancer

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Organ

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.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. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). 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 signalling 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. More help

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
DNA damage and metastatic breast cancer AdverseOutcome Usha Adiga (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. 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
human and other cells in culture human and other cells in culture High NCBI
human Homo sapiens High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
Adult High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Mixed High

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. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Biological state: 

Dissemination of the cancer cells from one organ to another which is not directly connected to the primary site is called metastasis. It has a crucial role in the prognosis of cancer patients. In the initial stage of metastasis, cancer cells detach from the primary tumor and disseminate in the tissue. Subsequently cancer cells enter the vascular or lymphatic channels (23-25). The establishment of micro-metastasis mainly depends on the survival of the circulating tumor cells (CTCs) inside the lymphatic or blood channels. Extravasation of cancer cells through the vessel wall takes place resulting in the proliferation of cancer cells in the secondary site.  Various signalling pathways are involved in each of the above mentioned   process. Few theories have been proposed to explain the mechanism of metastasis.  The organ selection concept theory suggests that the growth factors establish a successful metastasis in the metastatic site (26,27) whereas the “adhesion theory proposes the tissue specific adhesion molecules are expressed on endothelial cells of recipient organs  which will anchor the migrating cancer cells,  providing the a pre-metastatic niche. The role of chemokine receptor has been explained in chemo-attraction theory while Paget   reported the theory of seed for metastatic tumor cells and of soil for the secondary site. As per this concept the organ distribution is determined by the site and histopathological type of the primary tumor.  The recent understanding suggested, pre-metastatic niche has been indicated to explain metastasis.  It is interesting to note that prior to co-localization, the primary tumor induces the micro environment of secondary site by CTCs.

 Subsequently, a metastatic niche is generated to support disseminated tumor cells (DTCs) and localize them to develop a metastasis.  The most recent theory describes a bidirectional relationship between the primary and secondary sites. According to this theory, the surviving cancer cells in the metastatic tumor can return to the primary site to promote the primary tumor progression (28,29). Efficient and  direct  blood  flow  can  explain  the  probability  of metastasis  to  the  specific  organs  like  hepatic  metastasis in patients  with colon cancer which  receive direct blood  flow  from  the  primary  site .Vascular  permeability is also the other factor  which  significantly  promotes extravasation  at  the metastatic  site. However at present, understanding of molecular mechanisms of metastasis remains incomplete.

Biological compartment

Organs,Cellular

Role in general biology

Epithelial-  mesenchymal  transition  (EMT) and its reverse  mesenchymal-epithelial  transition (MET)  are characteristics  of cellular  plasticity  during embryogenesis  and  tumor metastasis  (30).  There has been decreased expression of  E-cadherin  and  β-catenin  and  elevated  expression  levels of  vimentin,  fibronectin  and  N-cadherin in EMT   (31).  In cancers, EMT  is a major  process  by which  cancer cells  lose their epithelial  characteristics  to acquire mesenchymal-like properties.  Tumor cell  migration  is a pre-requisite for the metastatic process in which, EMT is  the most critical step to  initiate  metastasis including metastasis to  lymph nodes  (32).  During   EMT, cancer  cells lose their  cell-to-cell junctions and cellular  polarity via multiple  signaling pathways which  increase  the motilities and invasive phenotype of them (33). Cleavage of  E-cadherin mediated by the MMPs  increases  the tumor cell  motility and invasion . Apart from this ,EMT has a  key role  in  drug resistance.  This is supported by the finding that  high levels of vimentin was found  in adriamycin and  vinblastine  resistant  breast  cancer cell  lines  (34). EMT  promotes CSCs  motility, cancer cell invasion, tumor  metastasis and recurrence and drug resistance.   Expression  of  stem cell like  markers  and formation of tumor spheres by CSCs are enhanced by EMT  process.  CSCs acquire mesenchymal  features by undergoing EMT phenomenon. By acquiring mesenchymal features,  CSCs become resistant  to anti-cancer therapies; hence, they can  survive and cause cancer recurrence.  In addition to this ,CSCs invade to the adjacent  stromal  tissues, enter the  vascular channels,  and  finally  reach  the  distant  organs.  In  the target organs, CSCs  cause MET phenomenon  which results in the acquisition of  epithelial  characteristics.  MET  phenomenon also   increases the  cell-to-cell attachment, cancer cells proliferation and differentiation to form  metastatic lesions  (35).  Altogether , EMT induces  CSC properties   and metastatic  activities. On the other hand, EMT  and CSCs collaborate in invasion capacity   hence targeting  the EMT/CSC  phenotype can be a therapeutic  approach for the treatment of metastasis and tumor recurrence (36).

EMT programs are regulated by a network of signal- ling pathways that involve components such as growth factors (transforming growth factor-β [TGF-β], epider- mal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt) in response to stresses involved in tumorigenesis, including hypoxia, oncogenic or metabolic stress, inflammation, and physical constraints [37-41].

These signals activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/ 2, and E12/E47 [42-44]. EMT-inducing transcription factors regulate the expression of proteins involved in cell polarity, cell-cell contact, cytoskeletal structural maintenance, and extracellular matrix (ECM) degradation, and they sup- press key epithelial genes. Loss of E-cadherin is considered a hallmark of EMT; these EMT-inducing transcription factors bind to E-box elements in the E-cadherin gene promoter to repress its transcription. Of particular note, Snail is an early marker of EMT that is involved in the initial cell-migratory phenotype, and it occasionally induces other factors .

During EMT, epithelial cells reorganize cytoskeleton and resolve cellcell junctions, which are accompanied with switching off the expression of epithelial markers and turning on mesenchymal genes. Although changes in epithelial and mesenchymal markers during EMT can vary significantly in different biologic contexts, a network of transcription factors, including TWIST1/2, SNAIL1/2, ZEB1/2, and FOXC2, are consistently required to orchestrate the EMT program (45). The expression of these transcription factors is associated with poor prognosis and distant metastasis in various human cancers has been documented in various studies. (46). Besides its role in promoting tumor cell invasion, EMT is shown to confer tumor cells with resistance to apoptosis  and anoikis (47), thus allowing cell survival in the blood stream after intravasation. EMT could also facilitate tumor cells' escape from the senescence program, especially through TWIST1 and ZEB1 (48,49). Furthermore, EMT has been shown to  cancer cells with cancer stem cell (CSC)like features, which further aid tumor dormancy and chemo resistance (50,51).Tumor samples or experimental tumor xenograft models have provided convincing evidence for the activation of EMT in various primary epithelial tumors in various studies. . Interestingly, more recent studies reveal a dynamic requirement of EMT in tumor metastasis: activation of EMT promotes local tumor invasion, intravasation, and extravasation of the systemic circulation, whereas reversion of EMT is essential to establish macrometatasis in distant organs (52,53).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. 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).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Method/ measurement reference

Reliability

Strength of evidence

Assay fit for purpose

Repeatability/ reproducibility

Direct measure

Cell line,humans,Human cell line studies

qRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, bioluminesence imaging,wound healing assay,Wound scratch & Transwell assay, Microarray,Immunofluorescence, Immunohistochemistry,

+

Strong

Yes

Yes

Yes

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Increased metastasis of cancerous cells  is known to be highly conserved throughout evolution and is present from humans to invertebrates.

Evidence for Perturbation by Stressor

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. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

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