Upstream eventEpithelial-mesenchymal transition, induced
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy||adjacent||High||Low|
|Homo sapiens||Homo sapiens||High||NCBI|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Some population of the cells exhibiting EMT demonstrates the feature of cancer stem cells (CSCs), which are related to cancer malignancy (Shibue & Weinberg, 2017; Shihori Tanabe, 2015a, 2015b; Tanabe, Aoyagi, Yokozaki, & Sasaki, 2015).
EMT phenomenon is related to cancer metastasis and cancer therapy resistance (Smith & Bhowmick, 2016; Tanabe, 2013). Increase expression of enzymes that degrade the extracellular matrix components and the decrease in adhesion to the basement membrane in EMT induce the cell escape from the basement membrane and metastasis (Smith & Bhowmick, 2016). Morphological changes observed during EMT is associated with therapy resistance (Smith & Bhowmick, 2016).
Evidence Supporting this KER
The morphological and physiological changes associated with EMT are involved in invasiveness and drug resistance (Shibue & Weinberg, 2017). The EMT-activated particular carcinoma cells in primary tumors invade the surrounding stroma (Shibue & Weinberg, 2017). The EMT –activated carcinoma cells interact with the surrounding extracellular matrix protein to induce focal adhesion kinase and extracellular signal-related kinase activation, followed by the transforming growth factor beta (TGFbeta) and canonical and/or noncanonical Wnt pathways to induce cancer stem cell (CSC) properties which contribute to the drug resistance (Shibue & Weinberg, 2017).
EMT-associated down-regulation of multiple apoptotic signaling pathways induce drug efflux and slow cell proliferation to induce the general resistance of carcinoma cells to anti-cancer drugs (Shibue & Weinberg, 2017).
Snail, an EMT-related transcription factor, induces the expression of the AXL receptor tyrosine kinase, which enables the cancer cells to survive by the activation of AXL signaling triggered by the binding of its ligand growth arrest-specific protein 6 (GAS6)(Shibue & Weinberg, 2017).
The EMT-activated cells evade the lethal effect of cytotoxic T cells, which include the elevated expression of programmed cell death 1 ligand (PD-L1) which binds to the programmed cell death protein 1 (PD-1) inhibitory immune-checkpoint receptor on the cell surface of cytotoxic T cells (Shibue & Weinberg, 2017).
Slug/Snai2, a ces-1-related zinc finger transcription factor gene, confers resistance to p53-mediated apoptosis of hematopoietic progenitors by repressing PUMA (also known as BBC3, encoding Bcl-2-binding component 3) (Inukai et al., 1999; Shibue & Weinberg, 2017; W.-S. Wu et al., 2005).
EMT activation induces the expression of multiple members of the ATP-binding cassette (ABC) transporter family, which results in the resistant to doxorubicin (Saxena, Stephens, Pathak, & Rangarajan, 2011; Shibue & Weinberg, 2017)
Snail-induced EMT induces the cancer metastasis and resistance to dendritic cell-mediated immunotherapy (Kudo-Saito, Shirako, Takeuchi, & Kawakami, 2009).
Zinc finger E-box-binding homeobox (ZEB1)-induced EMT results in the relief of miR-200-mediated repression of programmed cell death 1 ligand (PD-L1) expression, a major inhibitory ligand for the programmed cell death protein (PD-1) immune-checkpoint protein on CD8+ cytotoxic T lymphocyte (CTL), subsequently the CD8+ T cell immunosuppression and metastasis (Chen et al., 2014).
Uncertainties and Inconsistencies
The reversing process of EMT, which names as mesenchymal-epithelial transition (MET), may be 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).
Quantitative Understanding of the Linkage
Induction of EMT by TGFbeta and Twist increase the gene expression of EMT markers such as Snail, Vimentin, N-cadherin, and ABC transporters including ABCA3, ABCC1, ABCC3 and ABCC10 (Saxena et al., 2011).
Human mammary epithelial cells (HMLE) stably expressing Twist, FOXC2 or Snail demonstrates the increased the cell viability compared to control HMLE in the treatment with about 0.3, 3, 30 mM of doxorubicin, dose-dependently (Saxena et al., 2011).
The treatment with doxorubicin for 48 hours demonstrates the increase in the cell viability in Twist/FOXC2/Snail overexpressed HMLE compared to control HMLE (Saxena et al., 2011).
The inhibition of Twist or Zeb1 with small interference RNA (siRNA) induced the inhibition of the cell viability compared to control MDAMB231 cells treated with doxorubicin for 48 hours (Saxena et al., 2011).
Known modulating factors
ABC transporters which are related to drug resistance are overexpressed in the EMT-activated cells (Saxena et al., 2011). The expression of PD-L1, which binds to the PD-1 on the cytotoxic T cells, is up-regulated in EMT-activated cells, which results in the inhibition of cancer immunity and the resistance to cancer therapy (Shibue & Weinberg, 2017).
Known Feedforward/Feedback loops influencing this KER
The investigation of EMT-CSC relations is important to understand the relationship between EMT and cancer malignancy. Non-CSCs in cancer can spontaneously undergo EMT and dedifferentiate into new CSC, subsequently induce the regeneration of tumorigenic potential (Marjanovic, Weinberg, & Chaffer, 2013; Shibue & Weinberg, 2017).
The plastic CSC theory demonstrates the bidirectional conversions between non-CSCs and CSCs, which may contribute into the acquisition of cancer malignancy in EMT-activated cells (Marjanovic et al., 2013).
Domain of Applicability
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 communications, 5, 5241-5241. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25348003
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 Cell, 4(3), 343-352. Retrieved from http://www.sciencedirect.com/science/article/pii/S1097276500803366. doi:https://doi.org/10.1016/S1097-2765(00)80336-6
Kudo-Saito, C., Shirako, H., Takeuchi, T., & Kawakami, Y. (2009). Cancer Metastasis Is Accelerated through Immunosuppression during Snail-Induced EMT of Cancer Cells. Cancer Cell, 15(3), 195-206. Retrieved from http://www.sciencedirect.com/science/article/pii/S1535610809000324. doi:https://doi.org/10.1016/j.ccr.2009.01.023
Marjanovic, N. D., Weinberg, R. A., & Chaffer, C. L. (2013). Cell plasticity and heterogeneity in cancer. Clinical chemistry, 59(1), 168-179. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23220226
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 One, 6(6), e21548-e21548. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21738704
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 & disease, 2(7), e179-e179. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21734725
Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol, 14(10), 611-629. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28397828. doi:10.1038/nrclinonc.2017.44
Smith, B. N., & Bhowmick, N. A. (2016). Role of EMT in Metastasis and Therapy Resistance. J Clin Med, 5(2). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26828526. doi:10.3390/jcm5020017
Tanabe, S. (2013). Perspectives of gene combinations in phenotype presentation. World journal of stem cells, 5(3), 61-67. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23951387
Tanabe, S. (2015a). Origin of cells and network information. World journal of stem cells, 7(3), 535-540. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25914760
Tanabe, S. (2015b). Signaling involved in stem cell reprogramming and differentiation. World journal of stem cells, 7(7), 992-998. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26328015
Tanabe, S., Aoyagi, K., Yokozaki, H., & Sasaki, H. (2015). Regulated genes in mesenchymal stem cells and gastric cancer. World journal of stem cells, 7(1), 208-222. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25621121
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. Cell, 123(4), 641-653. Retrieved from http://www.sciencedirect.com/science/article/pii/S0092867405010317. doi:https://doi.org/10.1016/j.cell.2005.09.029