Microscopic and immunohistochemical characteristics of epithelial-mesenchymal transformation in ductal adenocarcinoma of the pancreas of moderate and low degrees of differentiation

Authors

DOI:

https://doi.org/10.26641/1997-9665.2023.4.60-73

Keywords:

immunohistochemistry, epithelial-mesenchymal, transformation, ductal adenocarcinoma, pancreas, differentiation, E-cadherin, β-catenin, CK7, CK18, αSMA, vimentin.

Abstract

Background. To date, there is no single protocol or guideline for the macro- and microscopic description of pancreatic ductal adenocarcinoma (PDAC), which is due to the heterogeneity within the tumor and its dispersed growth associated with the process of epithelial-mesenchymal transformation (EMT). Also, there are no data on the expression of EMT markers at different degrees of differentiation and features of their expression in the PDAC ducts and the EMT zone in the literature. Aim: quantitative immunohistochemical analysis of the expression of epithelial and mesenchymal markers in the glandular-ductal compartment and in the EMT zone of the PDAC of a moderate (G2) and low (G3) degree of differentiation. Methods. A complex pathomorphological, immunohistochemical study of operative and biopsy material of 49 patients with ductal adenocarcinoma of the pancreas with a moderate (G2) and low (G3) degree of differentiation was conducted. All research results were processed in the program«STATISTICA 13.0» (StatSoft Inc., license No. JPZ804I382130ARCN10-J). Results. During the histological examination, it was established that the histoarchitectonics of the PDAC consists of glandular-ductal and stromal compartments. According to the Masson-trichrome method, a statistically significant decrease in the area of trabecular and tubular structures and a statistically significant increase in the area of the fibrous stroma from G2 to G3 were established. In the G2-G3 sequence of the differentiation stage, a statistically significant decrease in the relative expression area of E-cadherin, CK7 and CK18 in the EMT zones was established in comparison with the glandular-ductal compartment, an inversely proportional expression of β-catenin in the transformation zones and in singly transformed cells, a statistical increase relative expression area of αSMA and vimentin in the stromal compartment. With a decrease in the relative expression area of epithelial markers in the EMT zones, there was an increase in the relative expression area of αSMA and vimentin in the G2-G3 sequence of the differentiation stage. Conclusion. From a moderate (G2) to a low (G3) degree of differentiation, a statistically significant (p<0.05) inversely proportional expression of epithelial and mesenchymal markers in the cells of the EMT zones is noted.

References

  1. Nicolle R, Blum Y, Duconseil P, Vanbrugghe C, Brandone N, Poizat F, Roques J, Bigonnet M, Gayet O, Rubis M, Elarouci N, Armenoult L, Ayadi M, de Reyniès A, Giovannini M, Grandval P, Garcia S, Canivet C, Cros J, Bournet B, Buscail L; BACAP Consortium; Moutardier V, Gilabert M, Iovanna J, Dusetti N. Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer. EBioMedicine. 2020;57:102858. doi:10.1016/j.ebiom.2020. 102858. PMCID: PMC7334821.
  2. Ren B, Liu X, Suriawinata AA. Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions: Histopathology, Cytopathology, and Molecular Pathology. Am J Pathol. 2019;189(1):9-21. doi:10.1016/j.ajpath.2018.10.004. PMID: 30558727.
  3. Haeberle L, Esposito I. Pathology of pancreatic cancer. Transl Gastroenterol Hepatol. 2019;4:50. doi:10.21037/tgh.2019.06.02. PMID: 31304427; PMCID: PMC6624347.
  4. Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ. A central role for cadherin signaling in cancer. Exp Cell Res. 2017;358(1):78-85. doi:10.1016/j.yexcr.2017.04.006. Epub 2017 Apr 12. PMID: 28412244; PMCID: PMC5544584.
  5. Safa AR. Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance. J Cancer Metastasis Treat. 2020;6:36. doi:10.20517/2394-4722.2020.55. Epub 2020 Sep 27. PMID: 34841087; PMCID: PMC8623975.
  6. Ribatti D, Tamma R, Annese T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol. 2020;13(6):100773. doi:10.1016/j.tranon.2020.100773. Epub 2020 Apr 22. PMID: 32334405; PMCID: PMC7182759.
  7. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018;12(4):361-373. doi:10.1007/s11684-018-0656-6. Epub 2018 Jul 24. PMID: 30043221; PMCID: PMC6186394.
  8. Lee AYL, Dubois CL, Sarai K, Zarei S, Schaeffer DF, Sander M, Kopp JL. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut. 2019;68(3):487-498. doi:10.1136/gutjnl-2017-314426. Epub 2018 Jan 23. PMID: 29363536.
  9. Romeo E, Caserta CA, Rumio C, Marcucci F. The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System. Cells. 2019;8(5):460. doi:10.3390/cells8050460. PMID: 31096701; PMCID: PMC6562673.
  10. Aiello NM, Maddipati R, Norgard RJ, Balli D, Li J, Yuan S, Yamazoe T, Black T, Sahmoud A, Furth EE, Bar-Sagi D, Stanger BZ. EMT Subtype Influences Epithelial Plasticity and Mode of Cell Migration. Dev Cell. 2018;45(6):681-695.e4. doi:10.1016/j.devcel.2018.05.027. PMID: 29920274; PMCID: PMC6014628.
  11. Liao TT, Yang MH. Hybrid Epithelial/Mesenchymal State in Cancer Metastasis: Clinical Significance and Regulatory Mechanisms. Cells. 2020;9(3):623. doi:10.3390/cells9030623. PMID: 32143517; PMCID: PMC7140395.
  12. Monkman JH, Thompson EW, Nagaraj SH. Targeting Epithelial Mesenchymal Plasticity in Pancreatic Cancer: A Compendium of Preclinical Discovery in a Heterogeneous Disease. Cancers (Basel). 2019;11(11):1745. doi:10.3390/cancers11111745. PMID: 31703358; PMCID: PMC6896204.
  13. Rodríguez Gil Y, Jiménez Sánchez P, Muñoz Velasco R, García García A, Sánchez-Arévalo Lobo VJ. Molecular Alterations in Pancreatic Cancer: Transfer to the Clinic. Int J Mol Sci. 2021;22(4):2077. doi:10.3390/ijms22042077. PMID: 33669845; PMCID: PMC7923218.
  14. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69-84. doi:10.1038/s41580-018-0080-4. PMID: 30459476.
  15. Kourtidis A, Lu R, Pence LJ, Anastasiadis PZ. A central role for cadherin signaling in cancer. Exp Cell Res. 2017;358(1):78-85. doi:10.1016/j.yexcr.2017.04.006. Epub 2017 Apr 12. PMID: 28412244; PMCID: PMC5544584.
  16. Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, Chong PP, Looi CY. The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells. 2019;8(10):1118. doi:10.3390/cells8101118. PMID: 31547193; PMCID: PMC6830116.
  17. Yu W, Yang L, Li T, Zhang Y. Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target. Front Oncol. 2019;9:989. doi:10.3389/fonc.2019.00989. PMID: 31637214; PMCID: PMC6788064.
  18. Sommariva M, Gagliano N. E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT. Cells. 2020;9(4):1040. doi:10.3390/cells9041040. PMID: 32331358; PMCID: PMC7226001.
  19. Wong SHM, Fang CM, Chuah LH, Leong CO, Ngai SC. E-cadherin: Its dysregulation in carcinogenesis and clinical implications. Crit Rev Oncol Hematol. 2018;121:11-22. doi:10.1016/j.critrevonc.2017.11.010. Epub 2017 Nov 20. PMID: 29279096.
  20. Baczynska D, Bombik I, Malicka-Błaszkiewicz M. β-Catenin Expression Regulates Cell Migration of Human Colonic Adenocarcinoma Cells Through Gelsolin. Anticancer Res. 2016;36(10):5249-5256. doi:10.21873/anticanres.11095. PMID: 27798885.
  21. Dmello C, Srivastava SS, Tiwari R, Chaudhari PR, Sawant S, Vaidya MM. Multifaceted role of keratins in epithelial cell differentiation and transformation. J Biosci. 2019;44(2):33. PMID: 31180046.
  22. Cheng Y, Qin K, Huang N, Zhou Z, Xiong H, Zhao J, Zhang Y, Yu S. Cytokeratin 18 regulates the transcription and alternative splicing of apoptotic related genes and pathways in HeLa cells. Oncol Rep. 2019;42(1):301-312. doi:10.3892/or.2019. 7166. Epub 2019 May 22. PMID: 31115582; PMCID: PMC6549092.
  23. Sousa B, Pereira J, Paredes J. The Crosstalk Between Cell Adhesion and Cancer Metabolism. Int J Mol Sci. 2019;20(8):1933. doi:10.3390/ ijms20081933. PMID: 31010154; PMCID: PMC6515343.
  24. Chen W, Hoffmann AD, Liu H, Liu X. Organotropism: new insights into molecular mechanisms of breast cancer metastasis. NPJ Precis Oncol. 2018;2(1):4. doi:10.1038/s41698-018-0047-0. PMID: 29872722; PMCID: PMC5871901.
  25. Battaglia RA, Delic S, Herrmann H, Snider NT. Vimentin on the move: new developments in cell migration. F1000Res. 2018;7:1000. doi:10.12688/f1000research.15967.1. PMID: 30505430; PMCID: PMC6241562.
  26. Palamaris K, Felekouras E, Sakellariou S. Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance. Cancers (Basel). 2021;13(21):5532. doi:10.3390/cancers13215532. PMID: 34771695; PMCID: PMC8582651.
  27. Sánchez-Ramírez D, Medrano-Guzmán R, Candanedo-González F, De Anda-González J, García-Rios LE, Pérez-Koldenkova V, Gutiérrez-de la Barrera M, Rodríguez-Enríquez S, Velasco-Velázquez M, Pacheco-Velázquez SC, Piña-Sánchez P, Mayani H, Gómez-Delgado A, Monroy-García A, Martínez-Lara AK, Montesinos JJ. High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma. Eur J Histochem. 2022;66(1):3360. doi:10.4081/ejh.2022. 3360. PMID: 35174683; PMCID: PMC8883614.

Published

2024-01-15

How to Cite

Shishkin , M., & Kabachenko , V. (2024). Microscopic and immunohistochemical characteristics of epithelial-mesenchymal transformation in ductal adenocarcinoma of the pancreas of moderate and low degrees of differentiation. Морфологія / Morphologia / Morfologìâ, 17(4), 60–73. https://doi.org/10.26641/1997-9665.2023.4.60-73

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