https://doi.org/10.4081/ejh.2022.3360
High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma
Submitted: 9 November 2021
Accepted: 9 February 2022
Published: 17 February 2022
Accepted: 9 February 2022
Abstract Views: 1769
PDF: 722
HTML: 26
HTML: 26
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Desmoplastic stroma (DS) and the epithelial-to-mesenchymal transition (EMT) play a key role in pancreatic ductal adenocarcinoma (PDAC) progression. To date, however, the combined expression of DS and EMT markers, and their association with variations in survival within each clinical stage and degree of tumor differentiation is unknown. The purpose of this study was to investigate the association between expression of DS and EMT markers and survival variability in patients diagnosed with PDAC. We examined the expression levels of DS markers alpha smooth muscle actin (α-SMA), fibronectin, and vimentin, and the EMT markers epithelial cell adhesion molecule (EPCAM), pan-cytokeratin, and vimentin, by immunohistochemistry using a tissue microarray of a retrospective cohort of 25 patients with PDAC. The results were examined for association with survival by clinical stage and by degree of tumor differentiation. High DS markers expression -α-SMA, fibronectin, and vimentin- was associated with decreased survival at intermediate and advanced clinical stages (p=0.006-0.03), as well as with both poorly and moderately differentiated tumor grades (p=0.01-0.02). Interestingly, the same pattern was observed for EMT markers, i.e., EPCAM, pan-cytokeratin, and vimentin (p=0.00008-0.03). High expression of DS and EMT markers within each clinical stage and degree of tumor differentiation was associated with lower PDAC survival. Evaluation of these markers may have a prognostic impact on survival time variation in patients with PDAC.
International Agency for Research on Cancer. Cancer today. Accessed: 6 June 2019. Available from: http://gco.iarc.fr/today/home
Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: Global trends, etiology and risk factors. World J Oncol 2019;10:10-27.
DOI: https://doi.org/10.14740/wjon1166
Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr J-M, Neoptolemos J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015;15:8-18.
DOI: https://doi.org/10.1016/j.pan.2014.10.001
Bilimoria KY, Bentrem DJ, Ko CY, Ritchey J, Stewart AK, Winchester DP, et al. Validation of the 6th edition AJCC pancreatic cancer staging system. Cancer 2007;110:738-44.
DOI: https://doi.org/10.1002/cncr.22852
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., Manual de estadificación del cáncer del AJCC. Springer; 2017.
Wasif N, Ko CY, Farrell J, Wainberg Z, Hines OJ, Reber H, et al. Impact of tumor grade on prognosis in pancreatic cancer: should we include grade in AJCC staging? Ann Surg Oncol 2010;17:2312-20.
DOI: https://doi.org/10.1245/s10434-010-1071-7
Ren H, Wu C-R, Qiu G-T, Zhang L-P, Aimaiti S, Wang C-F. Equipping the American Joint Committee on cancer staging for resectable pancreatic ductal adenocarcinoma with tumor grade: A novel staging system. J Oncol 2020;2020:9093729.
DOI: https://doi.org/10.1155/2020/9093729
Rochefort MM, Ankeny JS, Kadera BE, Donald GW, Isacoff W, Wainberg ZA, et al. Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system. Ann Surg Oncol 2013;20:4322-9.
DOI: https://doi.org/10.1245/s10434-013-3159-3
Hlavsa J, Cecka F, Zaruba P, Zajak J, Gurlich R, Strnad R, et al. Tumor grade as significant prognostic factor in pancreatic cancer: validation of a novel TNMG staging system. Neoplasma 2018;65:637-43.
DOI: https://doi.org/10.4149/neo_2018_171012N650
Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 2006;10:1199-210.
DOI: https://doi.org/10.1016/j.gassur.2006.08.018
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2004;363:1049-57.
DOI: https://doi.org/10.1016/S0140-6736(04)15841-8
Sperb N, Tsesmelis M, Wirth T. Crosstalk between tumor and stromal cells in pancreatic ductal adenocarcinoma. Int J Mol Sci 2020;21:e5486.
DOI: https://doi.org/10.3390/ijms21155486
Peran I, Madhavan S, Byers SW, McCoy MD. Curation of the pancreatic ductal adenocarcinoma subset of the cancer genome atlas is essential for accurate conclusions about survival-related molecular mechanisms. Clin Cancer Res 2018;24:3813-9.
DOI: https://doi.org/10.1158/1078-0432.CCR-18-0290
Waghray M, Yalamanchili M, Dziubinski M, Zeinali M, Erkkinen M, Yang H, et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov 2016;6:886-99.
DOI: https://doi.org/10.1158/2159-8290.CD-15-0947
Erkan M, Kleeff J, Gorbachevski A, Reiser C, Mitkus T, Esposito I, et al. Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 2007;132:1447-64.
DOI: https://doi.org/10.1053/j.gastro.2007.01.031
Omary MB, Lugea A, Lowe AW, Pandol SJ. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 2007;117:50-9.
DOI: https://doi.org/10.1172/JCI30082
Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016;22:2678-700.
DOI: https://doi.org/10.3748/wjg.v22.i9.2678
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998;115:421-32.
DOI: https://doi.org/10.1016/S0016-5085(98)70209-4
Eguchi D, Ikenaga N, Ohuchida K, Kozono S, Cui L, Fujiwara K, et al. Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor. J Surg Res 2013;181:225-33.
DOI: https://doi.org/10.1016/j.jss.2012.06.051
Vonlaufen A, Joshi S, Qu C, Phillips PA, Xu Z, Parker NR, et al. Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 2008;68:2085-93.
DOI: https://doi.org/10.1158/0008-5472.CAN-07-2477
Kalli M, Papageorgis P, Gkretsi V, Stylianopoulos T. Solid stress facilitates fibroblasts activation to promote pancreatic cancer cell migration. Ann Biomed Eng 2018;46:657-69.
DOI: https://doi.org/10.1007/s10439-018-1997-7
Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, et al. Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett 2016;372:210-8.
Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 2017;214:579-96.
DOI: https://doi.org/10.1084/jem.20162024
Li D, Qu C, Ning Z, Wang H, Zang K, Zhuang L, et al. Radiation promotes epithelial-to-mesenchymal transition and invasion of pancreatic cancer cell by activating carcinoma-associated fibroblasts. Am J Cancer Res 2016;6:2192-206.
Marrache F, Pendyala S, Bhagat G, Betz KS, Song Z, Wang TC. Role of bone marrow-derived cells in experimental chronic pancreatitis. Gut 2008;57:1113-20.
DOI: https://doi.org/10.1136/gut.2007.143271
Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 2004;64:8492-5.
DOI: https://doi.org/10.1158/0008-5472.CAN-04-1708
Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012;3:344.
DOI: https://doi.org/10.3389/fphys.2012.00344
von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A. The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 2017;10:76.
DOI: https://doi.org/10.1186/s13045-017-0448-5
Bulle A, Lim K-H. Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer. Signal Transduct Target Ther 2020;5:249.
DOI: https://doi.org/10.1038/s41392-020-00341-1
Bachem MG, Schünemann M, Ramadani M, Siech M, Beger H, Buck A, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005;128:907-21.
DOI: https://doi.org/10.1053/j.gastro.2004.12.036
Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 2010;177:2585-96.
DOI: https://doi.org/10.2353/ajpath.2010.090899
Manoukian P, Bijlsma M, van Laarhoven H. The cellular origins of cancer-associated fibroblasts and their opposing contributions to pancreatic cancer growth. Front Cell Dev Biol 2021;9:743907.
DOI: https://doi.org/10.3389/fcell.2021.743907
Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S, et al. Pancreatic stellate cells promote epithelial-mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 2010;403:380-4.
DOI: https://doi.org/10.1016/j.bbrc.2010.11.040
Hyun K-A, Koo G-B, Han H, Sohn J, Choi W, Kim S-I, et al. Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget 2016;7:24677-87.
DOI: https://doi.org/10.18632/oncotarget.8250
Maier HJ, Wirth T, Beug H. Epithelial-mesenchymal transition in pancreatic carcinoma. Cancers 2010;2:2058-83.
DOI: https://doi.org/10.3390/cancers2042058
Palamaris K, Felekouras E, Sakellariou S. Epithelial to mesenchymal transition: key regulator of pancreatic ductal adenocarcinoma progression and chemoresistance. Cancers 2021;13:5532.
DOI: https://doi.org/10.3390/cancers13215532
Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, et al. Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett 2016;372:210-8.
DOI: https://doi.org/10.1016/j.canlet.2016.01.016
Nemolato S, Restivo A, Cabras T, Coni P, Zorcolo L, Orrù G, et al. Thymosin β 4 in colorectal cancer is localized predominantly at the invasion front in tumor cells undergoing epithelial mesenchymal transition. Cancer Biol Ther 2012;13:191-7.
DOI: https://doi.org/10.4161/cbt.13.4.18691
Haeberle L, Cacciato Insilla A, Kapp A-C, Steiger K, Schlitter AM, Konukiewitz B, et al. Stroma composition and proliferative activity are related to therapy response in neoadjuvant treated pancreatic ductal adenocarcinoma. Histol Histopathol 2021;36:733-42.
Dardare J, Witz A, Merlin J-L, Bochnakian A, Toussaint P, Gilson P, et al. Epithelial to mesenchymal transition in patients with pancreatic ductal adenocarcinoma: State-of-the-art and therapeutic opportunities. Pharmaceuticals (Basel) 2021;14:740.
DOI: https://doi.org/10.3390/ph14080740
Stark AP, Sacks GD, Rochefort MM, Donahue TR, Reber HA, Tomlinson JS, et al. Long-term survival in patients with pancreatic ductal adenocarcinoma. Surgery 2016;159:1520-7.
DOI: https://doi.org/10.1016/j.surg.2015.12.024
He C, Zhang Y, Cai Z, Lin X, Li S. Overall survival, and cancer-specific survival in patients with surgically resected pancreatic head adenocarcinoma: A competing risk nomogram analysis. J Cancer 2018;9:3156-67.
DOI: https://doi.org/10.7150/jca.25494
Sinn M, Denkert C, Striefler JK, Pelzer U, Stieler JM, Bahra M, et al. α-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. Br J Cancer 2014;111:1917-23.
DOI: https://doi.org/10.1038/bjc.2014.495
Haeberle L, Steiger K, Schlitter AM, Safi SA, Knoefel WT, Erkan M, et al. Stromal heterogeneity in pancreatic cancer and chronic pancreatitis. Pancreatology 2018;18:1-14.
DOI: https://doi.org/10.1016/j.pan.2018.05.004
Fong D, Steurer M, Obrist P, Barbieri V, Margreiter R, Amberger A, et al. Ep-CAM expression in pancreatic and ampullary carcinomas: frequency and prognostic relevance. J Clin Pathol 2008;61:31-5.
DOI: https://doi.org/10.1136/jcp.2006.037333
Karamitopoulou E, Zlobec I, Born D, Kondi-Pafiti A, Lykoudis P, Mellou A, et al. Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Eur J Cancer 2013;49:1032-9.
DOI: https://doi.org/10.1016/j.ejca.2012.10.022
Matros E, Bailey G, Clancy T, Zinner M, Ashley S, Whang E, et al. Cytokeratin 20 expression identifies a subtype of pancreatic adenocarcinoma with decreased overall survival. Cancer 2006;106:693-702.
DOI: https://doi.org/10.1002/cncr.21609
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;2017;1-7.
DOI: https://doi.org/10.1155/2017/9207616
Muckenhuber A, Berger AK, Schlitter AM, Steiger K, Konukiewitz B, Trumpp A, et al. Pancreatic ductal adenocarcinoma subtyping using the biomarkers hepatocyte nuclear factor-1A and cytokeratin-81 correlates with outcome and treatment response. Clin Cancer Res 2018; 24:351-9.
DOI: https://doi.org/10.1158/1078-0432.CCR-17-2180
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
DOI: https://doi.org/10.3322/caac.21492
Bartlett JE, Kotrlik JW, Higgins CC. Organizational research: Determining appropriate sample size in survey research. Inf Technol Learn Perform J 2001;19:43-50.
Pacheco-Velázquez SC, Gallardo-Pérez JC, Díaz D, Adán-Ladrón de Guevara A, Robledo-Cadena DX, Saavedra E, et al. Heart myxoma develops oncogenic and metastatic phenotype. J Cancer Res Clin Oncol 2019;145:1283-95.
DOI: https://doi.org/10.1007/s00432-019-02897-0
Chan KS, Ho BCS, Shelat VG. A pilot study of estrogen receptor (ER) expression in pancreatic ductal adenocarcinoma (PDAC). Transl Gastroenterol Hepatol 2021;6:9.
DOI: https://doi.org/10.21037/tgh.2020.02.16
Hassan S, Ferrario C, Mamo A, Basik M. Tissue microarrays: emerging standard for biomarker validation. Curr Opin Biotechnol 2008;19:19-25.
DOI: https://doi.org/10.1016/j.copbio.2007.10.009
Santosh N, McNamara KK, Beck FM, Kalmar JR. Expression of cornulin in oral premalignant lesions. Oral Surg Oral Med Oral Pathol Oral Radiol 2019;127:526-34.
DOI: https://doi.org/10.1016/j.oooo.2019.02.003
Marinaccio C, Ribatti D. A simple method of image analysis to estimate CAM vascularization by APERIO ImageScope software. Int J Dev Biol 2015;59:217-9.
DOI: https://doi.org/10.1387/ijdb.150025dr
Diaz D, Vazquez-Polanco AM, Argueta-Donohue J, Stephens CR, Jimenez-Trejo F, Ceballos-Liceaga SE, et al. Incidence of Intestinal infectious diseases due to protozoa and bacteria in Mexico: Analysis of national surveillance records from 2003 to 2012. BioMed Res Int 2018;2018:2893012.
DOI: https://doi.org/10.1155/2018/2893012
Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle 2011;10:4047-64.
DOI: https://doi.org/10.4161/cc.10.23.18151
Maehira H, Miyake T, Iida H, Tokuda A, Mori H, Yasukawa D, et al. Vimentin expression in tumor microenvironment predicts survival in pancreatic ductal adenocarcinoma: Heterogeneity in fibroblast population. Ann Surg Oncol 2019;26:4791-804.
DOI: https://doi.org/10.1245/s10434-019-07891-x
Wang M, Estrella JS, Katz MH, Kim M, Rashid A, Lee JE, et al. Expression of epithelial-mesenchymal transition markers in treated pancreatic ductal adenocarcinoma. Pancreas 2019;48:1367-72.
DOI: https://doi.org/10.1097/MPA.0000000000001432
Javle MM, Gibbs JF, Iwata KK, Pak Y, Rutledge P, Yu J, et al. Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann Surg Oncol 2007;14:3527-33.
DOI: https://doi.org/10.1245/s10434-007-9540-3
Dhayat SA, Traeger MM, Rehkaemper J, Stroese AJ, Steinestel K, Wardelmann E, et al. Clinical impact of epithelial-to-mesenchymal transition regulating microRNAs in pancreatic ductal adenocarcinoma. Cancers 2018;10:1-20.
DOI: https://doi.org/10.3390/cancers10090328
Kohler I, Bronsert P, Timme S, Werner M, Brabletz T, Hopt UT, et al. Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma. J Gastroenterol Hepatol 2015;30:S78-84.
DOI: https://doi.org/10.1111/jgh.12752
Chouat E, Zehani A, Chelly I, Njima M, Maghrebi H, Bani MA, et al. Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review. Pancreatology 2018;18:79-84.
DOI: https://doi.org/10.1016/j.pan.2017.11.010
Hu D, Ansari D, Zhou Q, Sasor A, Said Hilmersson K, Andersson R. Stromal fibronectin expression in patients with resected pancreatic ductal adenocarcinoma. World J Surg Oncol 2019;17:29.
DOI: https://doi.org/10.1186/s12957-019-1574-z
Supporting Agencies
national science and technology council, coordination of health researchHow to Cite
Sánchez-Ramírez, D., Medrano-Guzmán, R., Candanedo-González, F., De Anda-González, J., García-Rios, L. E., Pérez-Koldenkova, V., … Montesinos, J. J. (2022). High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma. European Journal of Histochemistry, 66(1). https://doi.org/10.4081/ejh.2022.3360
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- V Barresi, M Grosso, G Bulfamante, E Vitarelli, MC Ghioni, G Barresi, Caveolin-1 immuno-expression in human fetal tissues during mid and late gestation , European Journal of Histochemistry: Vol. 50 No. 3 (2006)
- S Montagnani, L Postiglione, G Giordano-Lanza, F Di Meglio, C Castaldo, S Sciorio, N Montuori, G Di Spigna, P Ladogana, A Oriente, G Rossi, Granulocyte macrophage colony stimulating factor (GM-CSF) biological actions on human dermal fibroblasts , European Journal of Histochemistry: Vol. 45 No. 3 (2001)
You may also start an advanced similarity search for this article.
Publication Facts
Metric
This article
Other articles
Peer reviewers
2
2.4
Reviewer profiles N/A
Author statements
Author statements
This article
Other articles
Data availability
N/A
16%
External funding
N/A
32%
Competing interests
N/A
11%
Metric
This journal
Other journals
Articles accepted
57%
33%
Days to publication
99
145
- Editor & editorial board
- profiles
- Academic society
- N/A
- Publisher
- PAGEPress Publications, Pavia, Italy
To learn about these publication facts, click 
PF is maintained by the Public Knowledge Project
