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Event: 1982
Key Event Title
metastatic breast cancer
Short name
Biological Context
Level of Biological Organization |
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Organ |
Organ term
Key Event Components
Key Event Overview
AOPs Including This Key Event
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 Do not cite | Under Development |
Taxonomic Applicability
Life Stages
Life stage | Evidence |
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Adult | High |
Sex Applicability
Term | Evidence |
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Mixed | High |
Key Event Description
Processs: metastasis of cancer cells Object:metastasis Process:Increased
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 cell–cell 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
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
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
The Adverse Outcome Pathway (AOP) holds substantial regulatory significance as a structured framework for understanding and predicting the biological sequence of events leading from DNA damage to a metastatic breast cancer. By elucidating the causal relationships between key events along the pathway, AOP offer a comprehensive understanding of toxicological mechanisms and provide a basis for informed decision-making in risk assessment and regulatory decision-making. AOPs facilitate the integration of diverse scientific data, enabling regulators to evaluate the potential impact of chemical exposures on human health and the environment. These pathways empower the development of targeted testing strategies, alternative methods, and safer chemical design, ultimately enhancing the efficiency and accuracy of risk assessment and regulatory policies.
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