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Event: 1982

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. 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. More help
Metastasis, Breast Cancer
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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
Organ

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

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

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 Agnes Aggy (send email) Under development: Not open for comment. Do not cite Under Development

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
human and other cells in culture human and other cells in culture High NCBI
human Homo sapiens High NCBI

Life Stages

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

Sex Applicability

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

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

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

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

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

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

References

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

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Chen L, Mai W, Chen M, Hu J, Zhuo Z, Lei X, Deng L, Liu J, Yao N, Huang M, Peng Y, Ye W, Zhang D.(2017) Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacol Res. 123:130-142.

Chen Y, Wang DD, Wu YP, Su D, Zhou TY, Gai RH, Fu YY, Zheng L, He QJ, Zhu H, Yang B.(2017) MDM2 promotes epithelial-mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. Br J Cancer. 117(8):1192-1201.

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