Exploring the Molecular Mechanism of Cancer Metastasis Focus on Epithelial Mesenchymal Transition (EMT)

Sehar Rahim Gillani; Saifullah Khan Mahar; Quratulain Badar; Atiba Sardar; Amara; Imtiaz Ali Soomro

doi:10.70749/ijbr.v3i2.713

Authors

Sehar Rahim Gillani Shaheed Zulfikar Ali Bhutto Institute of Science and Technology University, Karachi, Sindh, Pakistan.
Saifullah Khan Mahar Shifa Ul Mulk Memorial Hospital, Hamdard University, Karachi, Sindh, Pakistan.
Quratulain Badar Department of Oncology, Ziauddin University and Hospital, Karachi, Sindh, Pakistan.
Atiba Sardar North Sichuan Medical College, China.
Amara Medical Emergency Resilience Foundation, Jacobabad, Sindh, Pakistan.
Imtiaz Ali Soomro Department of Surgery, Peoples University of Medical and Health Sciences, Nawabshah, Sindh, Pakistan.

DOI:

https://doi.org/10.70749/ijbr.v3i2.713

Keywords:

Epithelial-mesenchymal Transition, Cancer Stem Cells, EMT Markers, Snail, ZEB1, CD44, ALDH, Tumor Progression

Abstract

Epithelial-mesenchymal transition (EMT) is a significant event in cancer metastasis that involves the process of converting epithelial cells to a more migratory, mesenchymal state, thus playing a key role in tumor invasion and metastasis. In this study, the authors set out to investigate the molecular events of EMT in cancer with an emphasis on its relationship with cancer stem cells (CSCs). With a sample size of 31 patients with varying grades and tumor types, we performed a comparative analysis of expression levels of crucial EMT (Snail, Twist, ZEB1) and CSC (CD44, ALDH) markers by immunohistochemical staining. Statistical comparison was made using ANOVA and Kruskal-Wallis tests for determining differences in expression according to tumor grade and type. Furthermore, a multiple regression analysis was performed to determine the effect of different factors such as tumor grade, type, size, and patient demographics on marker expression. Results indicated significant variations in marker expression between tumor types and grades, with tumor grade and type having strong correlations with EMT and CSC marker expression. The results indicate that grade and tumor type are strong predictors of EMT and CSC features, which can play a role in drug resistance and metastatic ability seen in cancer. This work indicates the necessity to unravel mechanisms behind EMT and its role in cancer, and it can have implications in therapeutic treatments based on targeting the inhibition of EMT and CSC processes. This study highlights the link between tumor grade, type, and key EMT and CSC markers in cancer progression. Higher-grade tumors exhibit elevated Snail, Twist, ZEB1, CD44, and ALDH expression, promoting invasion and therapy resistance. Targeting these markers could improve treatments, but further research is needed to understand underlying molecular mechanisms.

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References

Foroni, C., Broggini, M., Generali, D., & Damia, G. (2012). Epithelial–mesenchymal transition and breast cancer: Role, molecular mechanisms and clinical impact. Cancer Treatment Reviews, 38(6), 689-697. https://doi.org/10.1016/j.ctrv.2011.11.001

Lamouille, S., Xu, J., & Derynck, R. (2014). Molecular mechanisms of epithelial–mesenchymal transition. Nature Reviews Molecular Cell Biology, 15(3), 178-196. https://doi.org/10.1038/nrm3758

Huang, J., Wang, J., Ramsey, E., Leavey, G., Chico, T. J., & Condell, J. (2022). Applying artificial intelligence to wearable sensor data to diagnose and predict cardiovascular disease: A review. Sensors, 22(20), 8002. https://doi.org/10.3390/s22208002

Yao, D., Dai, C., & Peng, S. (2011). Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Molecular Cancer Research, 9(12), 1608-1620. https://doi.org/10.1158/1541-7786.mcr-10-0568

Das, V., Bhattacharya, S., Chikkaputtaiah, C., Hazra, S., & Pal, M. (2019). The basics of epithelial–mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective. Journal of Cellular Physiology, 234(9), 14535-14555. https://doi.org/10.1002/jcp.28160

Yeung, K. T., & Yang, J. (2016). Epithelial–mesenchymal transition in tumor metastasis. Molecular Oncology, 11(1), 28-39. https://doi.org/10.1002/1878-0261.12017

Nieszporek, A., Skrzypek, K., Adamek, G., & Majka, M. (2019). Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis. Acta Biochimica Polonica. https://doi.org/10.18388/abp.2019_2899

Mittal, V. (2018). Epithelial Mesenchymal transition in tumor metastasis. Annual Review of Pathology: Mechanisms of Disease, 13(1), 395-412. https://doi.org/10.1146/annurev-pathol-020117-043854

Cho, E. S., Kang, H. E., Kim, N. H., & Yook, J. I. (2019). Therapeutic implications of cancer epithelial-mesenchymal transition (EMT). Archives of Pharmacal Research, 42(1), 14-24. https://doi.org/10.1007/s12272-018-01108-7

Meng, F., & Wu, G. (2012). The rejuvenated scenario of epithelial–mesenchymal transition (EMT) and cancer metastasis. Cancer and Metastasis Reviews, 31(3-4), 455-467. https://doi.org/10.1007/s10555-012-9379-3

Guarino, M., Rubino, B., & Ballabio, G. (2007). The role of epithelial-mesenchymal transition in cancer pathology. Pathology, 39(3), 305-318. https://doi.org/10.1080/00313020701329914

Roche, J. (2018). The epithelial-to-Mesenchymal transition in cancer. Cancers, 10(2), 52. https://doi.org/10.3390/cancers10020052

Talbot, L. J., Bhattacharya, S. D., & Kuo, P. C. (2012). Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. International journal of biochemistry and molecular biology, 3(2), 117. https://pmc.ncbi.nlm.nih.gov/articles/PMC3388731/

Datta, A., Deng, S., Gopal, V., Yap, K. C., Halim, C. E., Lye, M. L., Ong, M. S., Tan, T. Z., Sethi, G., Hooi, S. C., Kumar, A. P., & Yap, C. T. (2021). Cytoskeletal dynamics in epithelial-mesenchymal transition: Insights into therapeutic targets for cancer metastasis. Cancers, 13(8), 1882. https://doi.org/10.3390/cancers13081882

Usman, S., Waseem, N. H., Nguyen, T. K., Mohsin, S., Jamal, A., Teh, M., & Waseem, A. (2021). Vimentin is at the heart of epithelial Mesenchymal transition (EMT) mediated metastasis. Cancers, 13(19), 4985. https://doi.org/10.3390/cancers13194985

Jonckheere, S., Adams, J., De Groote, D., Campbell, K., Berx, G., & Goossens, S. (2021). Epithelial-mesenchymal transition (EMT) as a therapeutic target. Cells Tissues Organs, 211(2), 157-182. https://doi.org/10.1159/000512218

Jie, X., Zhang, X., & Xu, C. (2017). Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: Mechanisms and clinical applications. Oncotarget, 8(46), 81558-81571. https://doi.org/10.18632/oncotarget.18277

Khanbabaei, H., Ebrahimi, S., García-Rodríguez, J. L., Ghasemi, Z., Pourghadamyari, H., Mohammadi, M., & Kristensen, L. S. (2022). Non-coding RNAs and epithelial mesenchymal transition in cancer: Molecular mechanisms and clinical implications. Journal of Experimental & Clinical Cancer Research, 41(1). https://doi.org/10.1186/s13046-022-02488-x

Cannito, S., Novo, E., Di Bonzo, L. V., Busletta, C., Colombatto, S., & Parola, M. (2010). Epithelial–mesenchymal transition: From molecular mechanisms, redox regulation to implications in human health and disease. Antioxidants & Redox Signaling, 12(12), 1383-1430. https://doi.org/10.1089/ars.2009.2737

Creighton, C., Gibbons, D. L., & Jonathan M. Kurie. (2013). The role of epithelial–mesenchymal transition programming in invasion and metastasis: A clinical perspective. Cancer Management and Research, 187. https://doi.org/10.2147/cmar.s35171

Yang, J., Antin, P., Berx, G., Blanpain, C., Brabletz, T., Bronner, M., ... & EMT International Association (TEMTIA). (2020). Guidelines and definitions for research on epithelial–mesenchymal transition. Nature reviews Molecular cell biology, 21(6), 341-352. https://doi.org/10.1038/s41580-020-0237-9

Ashrafizadeh, M., Zarrabi, A., Hushmandi, K., Kalantari, M., Mohammadinejad, R., Javaheri, T., & Sethi, G. (2020). Association of the epithelial–mesenchymal transition (EMT) with cisplatin resistance. International Journal of Molecular Sciences, 21(11), 4002. https://doi.org/10.3390/ijms21114002

Mirzaei, S., Saghari, S., Bassiri, F., Raesi, R., Zarrabi, A., Hushmandi, K., Sethi, G., & Tergaonkar, V. (2022). NF‐κb as a regulator of cancer metastasis and therapy response: A focus on epithelial–mesenchymal transition. Journal of Cellular Physiology, 237(7), 2770-2795. https://doi.org/10.1002/jcp.30759

Lili, L. N., Matyunina, L. V., Walker, L. D., Wells, S. L., Benigno, B. B., & McDonald, J. F. (2013). Molecular profiling supports the role of epithelial-to-mesenchymal transition (EMT) in ovarian cancer metastasis. Journal of Ovarian Research, 6(1). https://doi.org/10.1186/1757-2215-6-49

Lee, J., & Kong, G. (2016). Roles and epigenetic regulation of epithelial–mesenchymal transition and its transcription factors in cancer initiation and progression. Cellular and Molecular Life Sciences, 73(24), 4643-4660. https://doi.org/10.1007/s00018-016-2313-z

Williams, E. D., Gao, D., Redfern, A., & Thompson, E. W. (2019). Controversies around epithelial–mesenchymal plasticity in cancer metastasis. Nature Reviews Cancer, 19(12), 716-732. https://doi.org/10.1038/s41568-019-0213-x

Silvestrini, V. C., Lanfredi, G. P., Masson, A. P., Poersch, A., Ferreira, G. A., Thomé, C. H., & Faça, V. M. (2019). A proteomics outlook towards the elucidation of epithelial–mesenchymal transition molecular events. Molecular Omics, 15(5), 316-330. https://doi.org/10.1039/c9mo00095j

Wesseling, M., Sakkers, T., de Jager, S., Pasterkamp, G., & Goumans, M. (2018). The morphological and molecular mechanisms of epithelial/endothelial-to-mesenchymal transition and its involvement in atherosclerosis. Vascular Pharmacology, 106, 1-8. https://doi.org/10.1016/j.vph.2018.02.006

Zavadil, J., Haley, J., Kalluri, R., Muthuswamy, S. K., & Thompson, E. (2008). Epithelial-mesenchymal transition. Cancer Research, 68(23), 9574-9577. https://doi.org/10.1158/0008-5472.can-08-2316

Gugnoni, M., & Ciarrocchi, A. (2019). Long Noncoding RNA and epithelial Mesenchymal transition in cancer. International Journal of Molecular Sciences, 20(8), 1924. https://doi.org/10.3390/ijms20081924

Moustakas, A., & Heldin, C. (2016). Mechanisms of tgfβ-induced epithelial–mesenchymal transition. Journal of Clinical Medicine, 5(7), 63. https://doi.org/10.3390/jcm5070063

Chui, M. H. (2012). Insights into cancer metastasis from a clinicopathologic perspective: Epithelial‐mesenchymal transition is not a necessary step. International Journal of Cancer, 132(7), 1487-1495. https://doi.org/10.1002/ijc.27745

Wendt, M. K., Allington, T. M., & Schiemann, W. P. (2009). Mechanisms of the epithelial–mesenchymal transition by TGF-β. Future Oncology, 5(8), 1145-1168. https://doi.org/10.2217/fon.09.90

Nantajit, D., Lin, D., & Li, J. J. (2014). The network of epithelial–mesenchymal transition: Potential new targets for tumor resistance. Journal of Cancer Research and Clinical Oncology, 141(10), 1697-1713. https://doi.org/10.1007/s00432-014-1840-y

Shakib, H., Rajabi, S., Dehghan, M. H., Mashayekhi, F. J., Safari-Alighiarloo, N., & Hedayati, M. (2019). Epithelial-to-mesenchymal transition in thyroid cancer: A comprehensive review. Endocrine, 66(3), 435-455. https://doi.org/10.1007/s12020-019-02030-8

Guarino, M. (2007). Epithelial–mesenchymal transition and tumour invasion. The International Journal of Biochemistry & Cell Biology, 39(12), 2153-2160. https://doi.org/10.1016/j.biocel.2007.07.011

Buyuk, B., Jin, S., & Ye, K. (2021). Epithelial-to-Mesenchymal transition signaling pathways responsible for breast cancer metastasis. Cellular and Molecular Bioengineering, 15(1), 1-13. https://doi.org/10.1007/s12195-021-00694-9

Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial dysfunction: A novel potential driver of epithelial-to-Mesenchymal transition in cancer. Frontiers in Oncology, 7. https://doi.org/10.3389/fonc.2017.00295

Drasin, D. J., Robin, T. P., & Ford, H. L. (2011). Breast cancer epithelial-to-mesenchymal transition: Examining the functional consequences of plasticity. Breast Cancer Research, 13(6). https://doi.org/10.1186/bcr3037

Creighton, C. J., Chang, J. C., & Rosen, J. M. (2010). Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. Journal of Mammary Gland Biology and Neoplasia, 15(2), 253-260. https://doi.org/10.1007/s10911-010-9173-1

Bracken, C. P., Gregory, P. A., Khew-Goodall, Y., & Goodall, G. J. (2009). The role of microRNAs in metastasis and epithelial-mesenchymal transition. Cellular and Molecular Life Sciences, 66(10), 1682-1699. https://doi.org/10.1007/s00018-009-8750-1

Steinestel, K., Eder, S., Schrader, A. J., & Steinestel, J. (2014). Clinical significance of epithelial‐mesenchymal transition. Clinical and Translational Medicine, 3(1). https://doi.org/10.1186/2001-1326-3-17

Grant, C. M., & Kyprianou, N. (2013). Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression. Translational andrology and urology, 2(3), 202. https://doi.org/10.3978/j.issn.2223-4683.2013.09.04

Mak, M. P., Tong, P., Diao, L., Cardnell, R. J., Gibbons, D. L., William, W. N., Skoulidis, F., Parra, E. R., Rodriguez-Canales, J., Wistuba, I. I., Heymach, J. V., Weinstein, J. N., Coombes, K. R., Wang, J., & Byers, L. A. (2016). A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial-to-Mesenchymal transition. Clinical Cancer Research, 22(3), 609-620. https://doi.org/10.1158/1078-0432.ccr-15-0876

Tang, M., Ren, P., & Zhao, Z. (2024). Bridging the gap: The role of educational technology in promoting educational equity. The Educational Review, USA, 8(8), 1077-1086. https://doi.org/10.26855/er.2024.08.012

McConkey, D. J., Choi, W., Marquis, L., Martin, F., Williams, M. B., Shah, J., Svatek, R., Das, A., Adam, L., Kamat, A., Siefker-Radtke, A., & Dinney, C. (2009). Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer and Metastasis Reviews, 28(3-4), 335-344. https://doi.org/10.1007/s10555-009-9194-7

Giannelli, G., Koudelkova, P., Dituri, F., & Mikulits, W. (2016). Role of epithelial to mesenchymal transition in hepatocellular carcinoma. Journal of Hepatology, 65(4), 798-808. https://doi.org/10.1016/j.jhep.2016.05.007

Thomson, S., Petti, F., Sujka-Kwok, I., Mercado, P., Bean, J., Monaghan, M., Seymour, S. L., Argast, G. M., Epstein, D. M., & Haley, J. D. (2010). A systems view of epithelial–mesenchymal transition signaling states. Clinical & Experimental Metastasis, 28(2), 137-155. https://doi.org/10.1007/s10585-010-9367-3

Rout-Pitt, N., Farrow, N., Parsons, D., & Donnelley, M. (2018). Epithelial mesenchymal transition (EMT): A universal process in lung diseases with implications for cystic fibrosis pathophysiology. Respiratory Research, 19(1). https://doi.org/10.1186/s12931-018-0834-8

Zhao, M., Kong, L., Liu, Y., & Qu, H. (2015). DbEMT: An epithelial-mesenchymal transition associated gene resource. Scientific Reports, 5(1). https://doi.org/10.1038/srep11459

Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation, 119(6), 1420-1428. https://doi.org/10.1172/jci39104

Serrano-Gomez, S. J., Maziveyi, M., & Alahari, S. K. (2016). Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications. Molecular Cancer, 15(1). https://doi.org/10.1186/s12943-016-0502-x

O’Connor, J. W., & Gomez, E. W. (2014). Biomechanics of tgfβ‐induced epithelial‐mesenchymal transition: Implications for fibrosis and cancer. Clinical and Translational Medicine, 3(1). https://doi.org/10.1186/2001-1326-3-23

Gooding, A. J., & Schiemann, W. P. (2020). Epithelial–mesenchymal transition programs and cancer stem cell phenotypes: Mediators of breast cancer therapy resistance. Molecular Cancer Research, 18(9), 1257-1270. https://doi.org/10.1158/1541-7786.mcr-20-0067

Feng, Y., Chen, D., Vaziri, N. D., Guo, Y., & Zhao, Y. (2019). Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis. Medicinal Research Reviews, 40(1), 54-78. https://doi.org/10.1002/med.21596

Iser, I. C., Pereira, M. B., Lenz, G., & Wink, M. R. (2016). The epithelial‐to‐Mesenchymal transition‐like process in glioblastoma: An updated systematic review and in Silico investigation. Medicinal Research Reviews, 37(2), 271-313. https://doi.org/10.1002/med.21408

Nistico, P., Bissell, M. J., & Radisky, D. C. (2012). Epithelial-mesenchymal transition: General principles and pathological relevance with special emphasis on the role of matrix Metalloproteinases. Cold Spring Harbor Perspectives in Biology, 4(2), a011908-a011908. https://doi.org/10.1101/cshperspect.a011908

Martinez, A. (2024). AI for Social Good: Leveraging Technology to Address Global Inequalities. Digital Transformation and Administration Innovation, 2(4), 18-23. https://journaldtai.com/index.php/jdtai/article/view/34