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Published in: Journal of Gastroenterology 2/2015

01-02-2015 | Review

Involvement of epithelial to mesenchymal transition in the development of pancreatic ductal adenocarcinoma

Authors: Kennichi Satoh, Shin Hamada, Tooru Shimosegawa

Published in: Journal of Gastroenterology | Issue 2/2015

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an intractable disease as a result of its rapid dissemination and resistance to conventional chemotherapy and radiotherapy. Surgical resection is the only curative therapy, but most of the tumors are unresectable at the time of diagnosis. The molecular mechanisms underlying the biological aggressiveness of this tumor type remain to be clarified. Epithelial to mesenchymal transition (EMT) is a developmental process that leads the phenotype shift from an epithelial morphology to a motile, fibroblast-like morphology. Recent studies showed that EMT is involved in the invasion and metastasis of many types of carcinomas including PDAC. In addition, PDAC cells with the EMT phenotype also exhibit chemoresistance and the cancer stem cell property. Various factors such as cytokines, growth factors, or transcriptional factors were found to promote the EMT program in PDAC cells. In this review, we summarize the current knowledge about the EMT in PDAC cells, focusing on the involvement of this process and its regulatory molecules including microRNA during the development of PDAC cells.
Literature
1.
go back to reference Matsuda A, Matsuda T, Shibata A, et al. A study of 25 population-based cancer registries for the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2013;44:388–96.CrossRef Matsuda A, Matsuda T, Shibata A, et al. A study of 25 population-based cancer registries for the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2013;44:388–96.CrossRef
3.
go back to reference Hong S, Park J, Hruban R, Goggins M. Molecular signatures of pancreatic cancer. Arch Pathol Lab Med. 2011;135:716–27. Hong S, Park J, Hruban R, Goggins M. Molecular signatures of pancreatic cancer. Arch Pathol Lab Med. 2011;135:716–27.
4.
go back to reference Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154:8–20.CrossRef Hay ED. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel). 1995;154:8–20.CrossRef
5.
go back to reference Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.PubMedCrossRef Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol. 2003;15:740–6.PubMedCrossRef
6.
go back to reference Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef Thiery JP. Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRef
7.
go back to reference Grünert S, Jechilinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol. 2003;4:657–65.PubMedCrossRef Grünert S, Jechilinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol. 2003;4:657–65.PubMedCrossRef
8.
go back to reference Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.PubMedCrossRef Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58.PubMedCrossRef
10.
go back to reference Wang Z, Li Y, Ahmad A, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8:27–33.PubMedCrossRef Wang Z, Li Y, Ahmad A, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8:27–33.PubMedCrossRef
11.
go back to reference Castellanos JA, Merchant NB, Nagathihalli NS. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther. 2013;6:1261–7.PubMedCentralPubMed Castellanos JA, Merchant NB, Nagathihalli NS. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther. 2013;6:1261–7.PubMedCentralPubMed
12.
go back to reference Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222–8.PubMed Ellenrieder V, Hendler SF, Boeck W, et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 2001;61:4222–8.PubMed
13.
go back to reference Yang AD, Camp ER, Fan F, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46–51.PubMedCrossRef Yang AD, Camp ER, Fan F, et al. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. Cancer Res. 2006;66:46–51.PubMedCrossRef
14.
go back to reference Wey JS, Fan F, Gray MJ, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–38.PubMedCrossRef Wey JS, Fan F, Gray MJ, et al. Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer. 2005;104:427–38.PubMedCrossRef
15.
go back to reference Hamada S, Satoh K, Hirota M, et al. Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line. J Cell Physiol. 2007;213:768–74.PubMedCrossRef Hamada S, Satoh K, Hirota M, et al. Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line. J Cell Physiol. 2007;213:768–74.PubMedCrossRef
16.
go back to reference Bo H, Zhang S, Gao Li, et al. Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells. BMC Cancer. 2013; doi: 10.1186/1471-2407-13-496. Bo H, Zhang S, Gao Li, et al. Upregulation of Wnt5a promotes epithelial-to-mesenchymal transition and metastasis of pancreatic cancer cells. BMC Cancer. 2013; doi: 10.​1186/​1471-2407-13-496.
17.
go back to reference Funamizu N, Hu C, Lacy C, et al. Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. Int J Cancer. 2012;132:785–94.CrossRef Funamizu N, Hu C, Lacy C, et al. Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. Int J Cancer. 2012;132:785–94.CrossRef
18.
go back to reference Satoh K, Hamada S, Kimura K, et al. Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. Am J Pathol. 2008;172:926–39.PubMedCentralPubMedCrossRef Satoh K, Hamada S, Kimura K, et al. Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. Am J Pathol. 2008;172:926–39.PubMedCentralPubMedCrossRef
19.
go back to reference Yamashita S, Miyagi C, Fukada T, et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature. 2004;429:298–302.PubMedCrossRef Yamashita S, Miyagi C, Fukada T, et al. Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature. 2004;429:298–302.PubMedCrossRef
20.
go back to reference Ikenouchi J, Matsuda M, Furuse M, et al. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116:1959–67.PubMedCrossRef Ikenouchi J, Matsuda M, Furuse M, et al. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003;116:1959–67.PubMedCrossRef
21.
go back to reference Unno J, Satoh K, Hirota M, et al. LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. Int J Oncol. 2009;35:813–21.PubMed Unno J, Satoh K, Hirota M, et al. LIV-1 enhances the aggressive phenotype through the induction of epithelial to mesenchymal transition in human pancreatic carcinoma cells. Int J Oncol. 2009;35:813–21.PubMed
22.
go back to reference von Burstin J, Eser S, Paul MC, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009;137:361–71.CrossRef von Burstin J, Eser S, Paul MC, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology. 2009;137:361–71.CrossRef
23.
go back to reference Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.PubMedCrossRef Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.PubMedCrossRef
24.
go back to reference Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesemchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.PubMedCrossRef Arumugam T, Ramachandran V, Fournier KF, et al. Epithelial to mesemchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.PubMedCrossRef
25.
go back to reference Shaah AN, Summy JM, Zhang J, et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.CrossRef Shaah AN, Summy JM, Zhang J, et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.CrossRef
26.
go back to reference Wang Z, Li Y, Kong D, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway. Cancer Res. 2009;69:2400–7.PubMedCentralPubMedCrossRef Wang Z, Li Y, Kong D, et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of Notch signaling pathway. Cancer Res. 2009;69:2400–7.PubMedCentralPubMedCrossRef
27.
go back to reference Güngör C, Zander H, Effenberger KE, et al. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res. 2011;71:5009–19.PubMedCrossRef Güngör C, Zander H, Effenberger KE, et al. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res. 2011;71:5009–19.PubMedCrossRef
28.
go back to reference Hamada S, Satoh K, Hirota M, et al. The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2. J Cell Physiol. 2012;227:729–38.PubMedCrossRef Hamada S, Satoh K, Hirota M, et al. The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2. J Cell Physiol. 2012;227:729–38.PubMedCrossRef
29.
go back to reference Salem AF, Bonuccelli G, Bevilacqua G, et al. Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition. Cell Cycle. 2011;10:3692–700.PubMedCentralPubMedCrossRef Salem AF, Bonuccelli G, Bevilacqua G, et al. Caveolin-1 promotes pancreatic cancer cell differentiation and restores membranous E-cadherin via suppression of the epithelial-mesenchymal transition. Cell Cycle. 2011;10:3692–700.PubMedCentralPubMedCrossRef
30.
go back to reference Reya T, Morrison S, Clarke M, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.PubMedCrossRef Reya T, Morrison S, Clarke M, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.PubMedCrossRef
31.
32.
go back to reference Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28.PubMedCrossRef Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28.PubMedCrossRef
33.
go back to reference Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.PubMedCrossRef Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.PubMedCrossRef
34.
go back to reference Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.PubMedCrossRef Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1:313–23.PubMedCrossRef
35.
go back to reference Kim MP, Fleming JB, Wang H, et al. ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One. 2011;6:e20636.PubMedCentralPubMedCrossRef Kim MP, Fleming JB, Wang H, et al. ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS One. 2011;6:e20636.PubMedCentralPubMedCrossRef
36.
go back to reference Li C, Wu JJ, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141:2218–27.PubMedCrossRef Li C, Wu JJ, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 2011;141:2218–27.PubMedCrossRef
38.
go back to reference Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011;307:26–36.PubMedCentralPubMedCrossRef Bao B, Wang Z, Ali S, et al. Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells. Cancer Lett. 2011;307:26–36.PubMedCentralPubMedCrossRef
39.
go back to reference Bao B, Wang Z, Ali S, et al. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem. 2011;112:2296–306.PubMedCentralPubMedCrossRef Bao B, Wang Z, Ali S, et al. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem. 2011;112:2296–306.PubMedCentralPubMedCrossRef
40.
41.
go back to reference Golebiewska A, Brons N, Bjerkvig R, et al. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell. 2011;8:136–47.PubMedCrossRef Golebiewska A, Brons N, Bjerkvig R, et al. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell. 2011;8:136–47.PubMedCrossRef
42.
43.
go back to reference Salnikov AV, Liu L, Platen M, et al. Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One. 2012;7:e46391.PubMedCentralPubMedCrossRef Salnikov AV, Liu L, Platen M, et al. Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One. 2012;7:e46391.PubMedCentralPubMedCrossRef
44.
go back to reference Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–52.PubMedCrossRef Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene. 2007;26:4442–52.PubMedCrossRef
46.
go back to reference Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.PubMedCrossRef Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.PubMedCrossRef
47.
go back to reference Li Y, VandenBoom TG 2nd, Kong D, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69:6704–12.PubMedCentralPubMedCrossRef Li Y, VandenBoom TG 2nd, Kong D, et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res. 2009;69:6704–12.PubMedCentralPubMedCrossRef
48.
go back to reference Hamada S, Satoh K, Fujibuchi W, et al. MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADM9. Mol Cancer Res. 2012;10:3–10.PubMedCrossRef Hamada S, Satoh K, Fujibuchi W, et al. MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADM9. Mol Cancer Res. 2012;10:3–10.PubMedCrossRef
49.
go back to reference Hamada S, Satoh K, Miura S, et al. MiR-197 induces epithelial-mesenchymal transition in pancreatic cancer cells by targeting p120 catenin. J Cell Physiol. 2013;228:1255–63.PubMedCrossRef Hamada S, Satoh K, Miura S, et al. MiR-197 induces epithelial-mesenchymal transition in pancreatic cancer cells by targeting p120 catenin. J Cell Physiol. 2013;228:1255–63.PubMedCrossRef
Metadata
Title
Involvement of epithelial to mesenchymal transition in the development of pancreatic ductal adenocarcinoma
Authors
Kennichi Satoh
Shin Hamada
Tooru Shimosegawa
Publication date
01-02-2015
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 2/2015
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-014-0997-0

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