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Relationship: 2614

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

EMT leads to Metastasis, Breast Cancer

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
EMT
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Alcohol Induced DNA damage and mutations leading to Metastatic Breast Cancer adjacent High High Usha Adiga (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 Do not cite Under Development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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  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

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult, reproductively mature Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Upstream event: Increased, EMT

Downstream event: Metastasis

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The “epithelial–mesenchymal transition” (EMT), a key developmental regulatory program, has been reported to play critical and intricate roles in promoting tumor invasion and metastasis in epithelium-derived carcinomas in recent years. The EMT program allows stationary and polarized epithelial cells, which are connected laterally via several types of junctions and normally interact with the basement membrane via their basal surfaces to maintain apical–basal polarity, to undergo multiple biochemical changes that enable them to disrupt cell–cell adherence, lose apical–basal polarity, dramatically remodel the cytoskeleton, and acquire mesenchymal characteristics such as enhanced migratory capacity, invasiveness, elevated resistance to apoptosis and greatly increased production of ECM components. (Boyer et al., 1993).Some of the cells undergoing EMT have the characteristics of cancer stem cells (CSCs), which are linked to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).Cancer metastasis and cancer therapeutic resistance are linked to the EMT phenomenon (Smith & Bhowmick, 2016; Tanabe, 2013). EMT causes the cell to escape from the basement membrane and metastasize by increasing the production of enzymes that breakdown extracellular matrix components and decreasing adherence to the basement membrane (Smith & Bhowmick, 2016). Therapy resistance is linked to morphological alterations seen during EMT (Smith & Bhowmick, 2016).

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Biological Plausibility

EMT is marked by a decrease in E-cadherin and β- -catenin translocation into the nucleus and an increase in vimentin, fibronectin, and N-cadherin expression (Irani et al., 2018,Tanabe et al., 2016). EMT is a master mechanism in cancer cells that allows them to lose their epithelial characteristics and gain mesenchymal-like qualities. EMT is the most crucial step in initiating metastasis, including metastasis to lymph nodes, because tumour cell movement is a pre-requisite for the metastatic process (Da et al., 2017). Multiple signalling pathways cause cancer cells to lose their cell-to-cell connections and cellular polarity during EMT, increasing their motility and invasive ness (Huang et al., 2017). MMPs cause E-cadherin to be cleaved, which increases tumour cell motility and invasion (Pradella et al., 2017).

Invasiveness and medication resistance are linked to the morphological and physiological changes associated with EMT (Shibue & Weinberg, 2017). In initial tumours, EMT-activated carcinoma cells penetrate the surrounding stroma (Shibue & Weinberg, 2017). EMT-activated carcinoma cells interact with the extracellular matrix protein to activate focal adhesion kinase and extracellular signal-related kinase, followed by TGFbeta and canonical and/or noncanonical Wnt pathways to develop cancer stem cell (CSC) traits, which contribute to drug resistance (Shibue & Weinberg, 2017).

Drug efflux and cell proliferation are slowed by EMT-associated downregulation of several apoptotic signalling pathways, resulting in general resistance of carcinoma cells to anti-cancer drugs (Shibue & Weinberg, 2017).Snail, an EMT-related transcription factor, promotes the production of the AXL receptor tyrosine kinase, which allows cancer cells to survive by activating AXL signalling when its ligand, growth arrest-specific protein 6 (GAS6), binds to it (Shibue & Weinberg, 2017).

EMT-activated cells are resistant to the deadly effects of cytotoxic T cells, which include increased expression of programmed cell death 1 ligand (PD-L1), which binds to the inhibitory immune-checkpoint receptor programmed cell death protein 1 (PD-1) on the cell surface of cytotoxic T cells(Shibue & Weinberg, 2017).

The reversing process of EMT, which names as a mesenchymal-epithelial transition (MET), maybe one of the candidates for the anti-cancer therapy, where the plasticity of the cell phenotype is of importance and under investigation (Shibue & Weinberg, 2017).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Whenever cell phenotype plasticity is crucial and under investigation, the reverse of EMT, known as the mesenchymal-epithelial transition (MET), may be one of the prospects for anti-cancer therapy (Shibue & Weinberg, 2017).

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

In EMT-activated cells, ABC transporters linked to drug resistance are overexpressed (Saxena et al., 2011). In EMT-activated cells, the expression of PD-L1, which binds to PD-1 on cytotoxic T cells, is upregulated, inhibiting cancer immunity and increasing resistance to cancer therapy (Shibue & Weinberg, 2017).

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

TGFbeta and Twist induce EMT by upregulating the expression of EMT markers such Snail, Vimentin, N-cadherin, and ABC transporters like ABCA3, ABCC1, ABCC3, and ABCC10 (Saxena et al., 2011).In the treatment with about 0.3, 3, 30 mM of doxorubicin, human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrate increased cell viability compared to control HMLE, dose-dependently (Saxena et al., 2011).

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

When Twist/FOXC2/Snail overexpressed HMLE is treated with doxorubicin for 48 hours, cell viability increases compared to control HMLE (Saxena et al., 2011).When Twist or Zeb1 were inhibited with small interference RNA (siRNA), cell viability was reduced relative to control MDAMB231 cells treated with doxorubicin for 48 hours (Saxena et al., 2011).

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help
  • Understanding the association between EMT and cancer malignancy necessitates further research into the EMT-cancer stem cells (CSC) relationship. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSCs, resulting in tumorigenic potential renewal (Marjanovic, Weinberg, & Chaffer, 2013; Shibue & Weinberg, 2017).The plastic CSC theory demonstrates bidirectional conversions between non-CSCs and CSCs, which could help EMT-activated cells acquire cancer malignancy (Marjanovic et al., 2013).
  • Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. Kong et al reported a novel lncRNA, LINC01133 that was downregulated by TGF- β, which could inhibit epithelial–mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC) cells (Kong et al.,2016). SRSF6, an alternative splicing factor that interacts directly with LINC01133, was found to enhance EMT and metastasis in CRC cells even when LINC01133 was not present. The study also found that the EMT process in CRC cells was regulated by LINC01133 in the presence of SRSF6. In vivo, the ability of LINC01133 to prevent metastasis was confirmed. Furthermore, clinical data revealed that LINC01133 expression was favourably correlated with E-cadherin and negatively correlated with Vimentin, and that low LIINC01133 expression in tumours was associated with poor CRC survival. These findings show that LINC01133, by directly binding to SRSF6 as a target mimic and inhibiting EMT and metastasis, could be used as a predictive biomarker and an effective target for anti-metastasis therapy in CRC.
  • MiR-148a inhibited Met expression directly by binding to its 30-UTR, according to Zhang et al's findings. Furthermore, reintroducing miR-148a reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT, by inhibiting Met's downstream signalling, such as activating phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3b-Ser9 (Zhang et al.,2015). MiR-148a, when combined, may suppress hepatoma cell EMT and metastasis by adversely regulating Met/Snail signalling.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

EMT induces cancer invasion, metastasis (Homo sapiens)(P. Zhang et al., 2015).

EMT is related to cancer drug resistance in MCF-7 human breast cancer cells (Homo sapiens)(B. Du & Shim, 2016).

References

List of the literature that was cited for this KER description. More help
  • BOYER, B., & THIERY, J. P. (1993). Epithelium‐mesenchyme interconversion as example of epithelial plasticity. Apmis101(1‐6), 257-268.

Chen, S. P., Liu, B. X., Xu, J., Pei, X. F., Liao, Y. J., Yuan, F., & Zheng, F. (2015). MiR-449a suppresses the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by multiple targets. BMC cancer15(1), 1-13.

  • Cui, B., Zhang, S., Chen, L., Yu, J., Widhopf, G. F., Fecteau, J. F., ... & Kipps, T. J. (2013). Targeting ROR1 inhibits epithelial–mesenchymal transition and metastasis. Cancer research73(12), 3649-3660.

Chen, Y., Wang, D. D., Wu, Y. P., Su, D., Zhou, T. Y., Gai, R. H., ... & Yang, B. (2017). MDM2 promotes epithelial–mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. British journal of cancer117(8), 1192-1201..

  • Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C. J., & Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer research71(1), 245-254.
  • Chen, L., Mai, W., Chen, M., Hu, J., Zhuo, Z., Lei, X., ... & Zhang, D. (2017). Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacological research123, 130-142.

Chen, L., Gibbons, D. L., Goswami, S., Cortez, M. A., Ahn, Y. H., Byers, L. A., ... & Qin, F. X. F. (2014). Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nature communications5(1), 1-12.

Da, C., Wu, K., Yue, C., Bai, P., Wang, R., Wang, G., ... & Hou, P. (2017). N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways. Oncotarget8(5), 8131.

Du, B., & Shim, J. S. (2016). Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer. Molecules21(7), 965.

  • Gao, J., Yang, Y., Qiu, R., Zhang, K., Teng, X., Liu, R., & Wang, Y. (2018). Proteomic analysis of the OGT interactome: novel links to epithelial–mesenchymal transition and metastasis of cervical cancer. Carcinogenesis39(10), 1222-1234.
  • Gumireddy, K., Li, A., Gimotty, P. A., Klein-Szanto, A. J., Showe, L. C., Katsaros, D., ... & Huang, Q. (2009). KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nature cell biology11(11), 1297-1304.
  • Gujral, T. S., Chan, M., Peshkin, L., Sorger, P. K., Kirschner, M. W., & MacBeath, G. (2014). A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell159(4), 844-856.

Huang, Y., Zhao, M., Xu, H., Wang, K., Fu, Z., Jiang, Y., & Yao, Z. (2014). RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis. Oncotarget5(16), 6734.

  • Huang, R., & Zong, X. (2017). Aberrant cancer metabolism in epithelial–mesenchymal transition and cancer metastasis: Mechanisms in cancer progression. Critical reviews in oncology/hematology115, 13-22.
  • Inukai, T., Inoue, A., Kurosawa, H., Goi, K., Shinjyo, T., Ozawa, K., ... & Look, A. T. (1999). SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Molecular cell4(3), 343-352.
  • Irani, S., & Dehghan, A. (2018). The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. Journal of International Society of Preventive & Community Dentistry8(2), 110.
  • Jackstadt, R., Röh, S., Neumann, J., Jung, P., Hoffmann, R., Horst, D., ... & Hermeking, H. (2013). AP4 is a mediator of epithelial–mesenchymal transition and metastasis in colorectal cancer. Journal of Experimental Medicine210(7), 1331-1350.
  • Kong, J., Sun, W., Li, C., Wan, L., Wang, S., Wu, Y., ... & Lai, M. (2016). Long non-coding RNA LINC01133 inhibits epithelial–mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. Cancer letters380(2), 476-484.
  • Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer cell15(3), 195-206.
  • Liang, Y. J., Wang, Q. Y., Zhou, C. X., Yin, Q. Q., He, M., Yu, X. T., ... & Zhao, Q. (2013). MiR-124 targets Slug to regulate epithelial–mesenchymal transition and metastasis of breast cancer. Carcinogenesis34(3), 713-722.
  • Liu, Y., Wang, G., Yang, Y., Mei, Z., Liang, Z., Cui, A., ... & Cui, L. (2016). Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner. Oncogene35(21), 2789-2800.

Liu, M., Xiao, Y., Tang, W., Li, J., Hong, L., Dai, W., ... & Xiang, L. (2020). HOXD9 promote epithelial‐mesenchymal transition and metastasis in colorectal carcinoma. Cancer medicine9(11), 3932-3943.

Marjanovic, N. D., Weinberg, R. A., & Chaffer, C. L. (2013). Cell plasticity and heterogeneity in cancer. Clinical chemistry59(1), 168-179.

  • Pirozzi, G., Tirino, V., Camerlingo, R., Franco, R., La Rocca, A., Liguori, E., ... & Rocco, G. (2011). Epithelial to mesenchymal transition by TGFβ-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PloS one6(6), e21548.
  • Pradella, D., Naro, C., Sette, C., & Ghigna, C. (2017). EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Molecular cancer16(1), 1-19.
  • Sarkar, T. R., Battula, V. L., Werden, S. J., Vijay, G. V., Ramirez-Peña, E. Q., Taube, J. H., ... & Mani, S. A. (2015). GD3 synthase regulates epithelial–mesenchymal transition and metastasis in breast cancer. Oncogene34(23), 2958-2967.
  • Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell death & disease2(7), e179-e179.
  • Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nature reviews Clinical oncology14(10), 611-629.
  • Shiota, M., Zardan, A., Takeuchi, A., Kumano, M., Beraldi, E., Naito, S., ... & Gleave, M. E. (2012). Clusterin mediates TGF-β–induced epithelial–mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer research72(20), 5261-5272.
  • Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in metastasis and therapy resistance. Journal of clinical medicine5(2), 17.
  • Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. World journal of stem cells5(3), 61.
  • Tanabe, S. (2015). Origin of cells and network information. World journal of stem cells7(3), 535.
  • Tanabe, S. (2015). Signaling involved in stem cell reprogramming and differentiation. World journal of stem cells7(7), 992.
  • Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2016). Regulation of CTNNB1 signaling in gastric cancer and stem cells. World journal of gastrointestinal oncology8(8), 592–598.
  • Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. World journal of stem cells7(1), 208.
  • Wang, L., Tong, X., Zhou, Z., Wang, S., Lei, Z., Zhang, T., ... & Zhang, H. T. (2018). Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer. Molecular cancer17(1), 1-18.
  • Wu, W. S., Heinrichs, S., Xu, D., Garrison, S. P., Zambetti, G. P., Adams, J. M., & Look, A. T. (2005). Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell123(4), 641-653.
  • Yu, C. P., Yu, S., Shi, L., Wang, S., Li, Z. X., Wang, Y. H., ... & Liang, J. (2017). FoxM1 promotes epithelial-mesenchymal transition of hepatocellular carcinoma by targeting Snai1. Molecular medicine reports16(4), 5181-5188.
  • Yu, J., Lei, R., Zhuang, X., Li, X., Li, G., Lev, S., ... & Hu, G. (2016). MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells. Nature communications7(1), 1-12.
  • Yue, B., Song, C., Yang, L., Cui, R., Cheng, X., Zhang, Z., & Zhao, G. (2019). METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer. Molecular cancer18(1), 1-15.
  • Zhang, P., Sun, Y., & Ma, L. (2015). ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell cycle14(4), 481-487.
  • Zhang, J. P., Zeng, C., Xu, L., Gong, J., Fang, J. H., & Zhuang, S. M. (2014). MicroRNA-148a suppresses the epithelial–mesenchymal transition and metastasis of hepatoma cells by targeting Met/Snail signaling. Oncogene33(31), 4069-4076.
  • Zhang, W., Shi, X., Peng, Y., Wu, M., Zhang, P., Xie, R., ... & Wang, J. (2015). HIF-1α promotes epithelial-mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PloS one10(6), e0129603.