Characteristics of the fibrous stroma in ductal adenocarcinoma of the pancreas depending on tumor size

Authors

  • M.A. Shyshkin
  • V.O. Kabachenko

Keywords:

ductal adenocarcinoma, pancreas, fibrous stroma, immunohistochemistry, alpha-SMA, vimentin.

Abstract

Background. Ductal adenocarcinoma of the pancreas (PDAC) is characterized by a pronounced dense fibrous stroma. There are conflicting data on the role of fibrous stroma in carcinogenesis, as the final mechanisms of interaction of cancer cells and stroma have not been definitively studied. Objective: to substantiate the strategic importance of timely comprehensive assessment of histochemical and immunohistochemical parameters of expression of mesenchymal markers of fibrous stroma response (α-SMA, vimentin) in PDAC in tumors up to 3 cm and more than 3 cm. Methods. Complex pathomorphological and immunohistochemical study of 49 cases of surgical material (tumors larger than 3 and less than 3 cm) in patients with ductal adenocarcinoma of the pancreas. All research results are processed in the program "STATISTICA 13.0" (StatSoft Inc., license No. JPZ804I382130ARCN10-J). Results. Histological examination revealed that the histoarchitectonics of PDAC consists of a cancer-duct compartment and fibrous stroma. Histochemical examination (Masso-trichrome staining) revealed a significantly significant development of fibrous stroma in tumors larger than 3 cm - Me=73.15% (Q1= 59.46; Q3=77.69), in tumors less than 3 cm - Me=28.73% (Q1=15.88; Q3=42.43) (p<0,05). The increase in the area of the fibrous stroma with the progression of the oncological process is accompanied by a significant increase in the expression of α-SMA in fibroblasts and activated pancreatic stellate cells that had diffuse brown membrane-cytoplasmic staining. The relative area of the marker in tumors less than 3 cm was Me=19.49% (Q1=12.71; Q3=28.85), in the second group - Me=27.78% (Q1=18.03; Q3=34, 24) (p<0,05). Vimentin expression was also manifested by diffuse membrane-cytoplasmic brown staining in fibroblasts and myofibroblasts without significant difference in groups. Relative area in the first group - Me=27.62% (Q1=21.34; Q3=43.82), in the second group - Me=24.39% (Q1=13.19; Q3=34.62) (p> 0.05). Conclusion. PDAC is characterized by significant development of fibrous stroma, more pronounced in tumors larger than 3 cm, where there is a significant prevalence of fibrous stroma over the cancerous duct compartment of the tumor, compared with tumors less than 3 cm.

References

  1. Tumanskiy VA, Evseyev AV, Kovalenko IS. Kolichestvennye pokazateli ekspressii stromal'nykh markerov v podzheludochnoi zheleze pri protokovoi adenokartsinome i khronicheskom pankreatite [Quantitative indexes of stromal markers expression in the patcreatic ductal adenocarcinoma and chronic pancreatitis]. Pathologia. 2015;2:26-30. Russian. doi.org/10.14739/2310-1237.2015.2.48621.
  2. Shyshkin MA, Fen SV. Epitelialno-mezenkhimalnyi perekhod v progressii kolorektalnoi adenokartsinomy [Epithelial-mesenchymal transition in сolorectal adenocarcinoma progression]. Zaporozhye Medical Journal. 2020;22(5):694-700. Russian. doi.org/10.14739/2310-1210.2020.5.214747.
  3. Ercan G, Karlitepe A, Ozpolat B. Pancreatic Cancer Stem Cells and Therapeutic Approaches. Anticancer Res. 2017;37(6):2761-75. DOI: 10.21873/anticanres.11628
  4. Front. Cell Dev. Biol., 25 November 2021 https://doi.org/10.3389/fcell.2021.787485 Targeting Tumor-Stromal Interactions in Pancreatic Cancer: Impact of Collagens and Mechanical Traits Parniyan Maneshi, James Mason, Mitesh Dongre and Daniel Öhlund
  5. Aiello N. M. et al. Metastatic progression is associated with dynamic changes in the local microenvironment. Nat. Commun. 7:12819 doi: 10.1038/ncomms12819 (2016). Nat Commun 7, 12819 (2016). https://doi.org/10.1038/ncomms12819 Metastatic progression is associated with dynamic changes in the local microenvironment Nicole M. Aiello, David L. Bajor, Robert J. Norgard, Amine Sahmoud, Neha Bhagwat, Minh N. Pham, Toby C. Cornish,Christine A. Iacobuzio-Donahue, Robert H. Vonderheide Ben Z. Stanger
  6. Biomark Res. 2021; 9: 47. Published online 2021 Jun 10. doi: 10.1186/s40364-021-00305-9 PMCID: PMC8194104 PMID: 34112258 Metastasis-associated fibroblasts: an emerging target for metastatic cancer Zimu Wang, Jiaxin Liu, Hairong Huang, Mingxiang Ye, Xinying Li, Ranpu Wu, Hongbing Liu, and Yong Song
  7. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies Aleksandra Adamska, Alice Domenichini and Marco Falasca Int. J. Mol. Sci. 2017, 18(7), 1338; https://doi.org/10.3390/ijms18071338
  8. Saini, F.; Argent, R.H.; Grabowska, A.M. Sonic Hedgehog Ligand: A Role in Formation of a Mesenchymal Niche in Human Pancreatic Ductal Adenocarcinoma. Cells 2019, 8, 424. [CrossRef]
  9. Cannon, A.; Thompson, C.; Hall, B.R.; Jain, M.; Kumar, S.; Batra, S.K. Desmoplasia in pancreatic ductal adenocarcinoma: Insight into pathological function and therapeutic potential. Genes Cancer 2018, 9, 78–86. PMID: 30108679 PMCID: PMC6086006 doi: 10.18632/genesandcancer.171. [PubMed]
  10. Alkasalias, T.; Moyano-Galceran, L.; Arsenian-Henriksson, M.; Lehti, K. Fibroblasts in the tumor microenvironment: Shield or spear? Int. J. Mol. Sci. 2018, 19, 1532. [CrossRef] [PubMed]
  11. Kuzet S. E., Gaggioli C. Fibroblast activation in cancer: when seed fertilizes soil. Cell and Tissue Research. 2016. Vol. 365. Issue 3. P. 607-619. https://doi.org/10.1007/s00441-016-2467-x
  12. Cells. 2018 Oct 5;7(10):158. doi: 10.3390/cells7100158. Tumor-Stroma Cross-Talk in Human Pancreatic Ductal Adenocarcinoma: A Focus on the Effect of the Extracellular Matrix on Tumor Cell Phenotype and Invasive Potential Patrizia Procacci 1, Claudia Moscheni 2, Patrizia Sartori 3, Michele Sommariva 4, Nicoletta Gagliano 5 PMID: 30301152 PMCID: PMC6209911 DOI: 10.3390/cells7100158 Cells 2018, 7(10), 158; https://doi.org/10.3390/cells7100158
  13. Topalovski M., Brekken R.A. Matrix control of pancreatic cancer: New insights into fibronectin signaling. Cancer Lett. 2016 Oct 10; 381 (1): 252–8. doi: 10.1016/j.canlet.2015.12.027.
  14. Liu, T.; Zhou, L.; Li, D.; Andl, T.; Zhang, Y. Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment. Front. Cell Dev. Biol. 2019, 7, 60. [CrossRef]
  15. Extracellular Matrix Alterations in Metastatic Processes Mayra Paolillo and Sergio Schinelli Int. J. Mol. Sci. 2019, 20, 4947; doi:10.3390/ijms20194947 www.mdpi.com/journal/ijms
  16. Wells, A.; Nuschke, A.; Yates, C.C. Skin tissue repair: Matrix microenvironmental influences. Matrix Biol. 2016, 49, 25–36. [CrossRef]
  17. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies Aleksandra Adamska, Alice Domenichini and Marco Falasca Int. J. Mol. Sci. 2017, 18(7), 1338; https://doi.org/10.3390/ijms18071338
  18. Høye, A.M.; Erler, J.T. Structural ECM components in the premetastatic and metastatic niche. Am. J. Physiol. Cell Physiol. 2016, 310, 955–967. [CrossRef] [PubMed]
  19. Walker, C.; Mojares, E.; Del Río Hernández, A. Role of Extracellular Matrix in Development and Cancer Progression. Int. J. Mol. Sci. 2018, 19, 3028. [CrossRef]
  20. Oxford, J.T.; Reeck, J.C.; Hardy, M.J. Extracellular Matrix in Development and Disease. Int. J. Mol. Sci. 2019, 20, 205. [CrossRef]
  21. M. Son et al. (2019) Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer / G. M. Son et al. Medicine. 2019. Vol. 98. Issue 18. P. e15164. https://doi.org/10.1097/ MD.0000000000015164.
  22. Laklai, H.; Miroshnikova, Y.A.; Pickup, M.W.; Collisson, E.A.; Kim, G.E.; Barrett, A.S.; Hill, R.C.; Lakins, J.N.; Schlaepfer, D.D.; Mouw, J.K.; et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 2016, 22, 497–505. [CrossRef]
  23. J. Hanley et al. (2016), 15 A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers Oncotarget. 2016; 7:6159-6174. https://doi.org/10.18632/oncotarget.6740 https://www.pathologyoutlines.com/topic/stainsvimentin.html
  24. Hyun Ju Hwang, Min-Suk Oh, Dong Woo Lee, Hyo-Jeong Kuh Multiplex quantitative analysis of stroma-mediated cancer cell invasion, matrix remodeling, and drug response in a 3D co-culture model of pancreatic tumor spheroids and stellate cells J Exp Clin Cancer Res 2019 Jun 14;38(1):258. doi: 10.1186/s13046-019-1225-9. PMID: 31200779 PMCID: PMC6567511 DOI: 10.1186/s13046-019-1225-924.
  25. Myoteri D, Dellaportas D, Lykoudis PM, Apostolopoulos A, Marinis A, Zizi-Sermpetzoglou A. Prognostic Evaluation of Vimentin Expression in Correlation with Ki67 and CD44 in Surgically Resected Pancreatic Ductal Adenocarcinoma. Gastroenterol Res Pract. 2017:9207616. Published online 2017 Mar 22. doi: 10.1155/2017/9207616.
  26. Battaglia RA, Delic S, Herrmann H, Snider NT. Vimentin on the move: new developments in cell migration. Faculty Rev. Research. 2018;7:1796. https://doi.org/10.12688/ f1000research.15967.
  27. Meyer SN. Co-expression of cytokeratin and vimentin in colorectal cancer highlights a subset of tumor buds and an atypical cancer-associated stroma. Human Pathology. 2019;87:18-27. doi.org/10.1016/j.humpath.2019.02.002
  28. Du L, Li J, Lei L. High vimentin expression predicts a poor prognosis and progression in colorectal cancer: a study with meta-analysis and TCGA database. Biomed Res Int. 2018;2018:6387810. DOI: 10.1155/2018/6387810.
  29. Najafi M,, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J. Cell Biochem. 2019;120:2782–90.
  30. Wu Q, Tian Y, Zhang J, Zhang H, Gu F, Lu Y. Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. Oncotarget. 2017;8:102721–38 doi: 10.18632/oncotarget.21970 PMCID: PMC5731993 PMID: 29254283.
  31. Danielsson F. Vimentin Diversity in Health and Disease. Cells. 2018;7(10):147. doi.org/10.3390/cells7100147.
  32. Maehira H, Miyake T, Iida H, Tokuda A, Mori H, Yasukawa D, Mukaisho K, Shimizu K, Tani M. Vimentin Expression in Tumor Microenvironment Predicts Survival in Pancreatic Ductal Adenocarcinoma: Heterogeneity in Fibroblast Population. Ann Surg Oncol. 2019;26(13):4791-4804. doi: 10.1245/s10434-019-07891-x.
  33. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018;15:366–81. doi: 10.1038/s41571-018-0007-1.

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Published

2022-05-25

How to Cite

Shyshkin , M., & Kabachenko, . V. . (2022). Characteristics of the fibrous stroma in ductal adenocarcinoma of the pancreas depending on tumor size. Морфологія / Morphologia / Morfologìâ, 16(2), 51–59. Retrieved from https://morphology.dma.edu.ua/article/view/282020

Issue

Vol. 16 No. 2 (2022)

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