The Truth Behind Esophagus: The Stem Cells’ Significance

  • Maximos Frountzas
  • Dimitrios Schizas
  • Alkistis Kapelouzou
  • Theodoros Liakakos
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


The presence of a continuously renewing squamous cell epithelium that covers the esophagus demonstrates the crucial role of a pluripotent stem cell population that regulates esophageal homeostasis and pathogenesis of the most esophageal diseases. Esophageal development and maintenance of adult esophageal homeostasis share common mechanisms, as transformation of early columnar esophageal epithelium into mature squamous epithelial cells is based on molecular regulators such as SOX2, p63, Notch, and NANOG, which are also present in fetal esophageal development. In addition, esophageal cancer seems to be associated with the cancer stem cell hypothesis, which refers to mutated pluripotent stem cell populations that give rise to cancerous cell accumulations. These mutations have been related to stem cell markers like aldehyde dehydrogenase-1 (ALDH1), Lgr5, Wnt/β-catenin, Notch, CD44, and CD177. Dietary habits, like alcohol consumption, and caustic injury of the esophagus have been correlated to such mutations and consequent carcinogenesis. Moreover, Barrett’s esophagus due to gastroesophageal reflux disease (GERD), which is a precancerous lesion that leads to esophageal adenocarcinoma, rises from either a native squamous esophageal stem cell population that turns into intestinal epithelial cell (transdifferentiation) or an intestinal esophageal stem cell population derived from the esophagus, stomach, or circulation (transcommitment), which turns immortal due to mutations in the stem cell markers Sox9, Sox2, p63, Cdx1, Cdx2, and Foxa2. Nevertheless, esophageal cancer stem cell-regulating molecules could be ideal pharmaceutic targets for future therapeutic attempts against esophageal cancer. Furthermore, stem cell technology could enhance tissue-engineering esophageal scaffolds in order to replace damaged esophageal segments with transplanted artificial segments, after radical surgical operations due to esophageal cancer, massive esophageal caustic injury, endoscopic esophageal dissection due to Barrett’s esophagus, ionizing radiation, and pediatric diseases, such as esophageal atresia or tracheoesophageal fistula.


Esophagus Stem Cell Barrett Scaffold 


  1. 1.
    Alcolea MP. Oesophageal stem cells and cancer. Adv Exp Med Biol. 2017;1041:187–206.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Alcolea MP, Greulich P, Wabik A, Frede J, Simons BD, Jones PH. Differentiation imbalance in single oesophageal progenitor cells causes clonal immortalization and field change. Nat Cell Biol. 2014;16:615–22.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Badylak SF, Hoppo T, Nieponice A, Gilbert TW, Davison JM, Jobe BA. Esophageal preservation in five male patients after endoscopic inner-layer circumferential resection in the setting of superficial cancer: a regenerative medicine approach with a biologic scaffold. Tissue Eng Part A. 2011;17:1643–50.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Barbera M, di Pietro M, Walker E, Brierley C, MacRae S, Simons BD, Jones PH, Stingl J, Fitzgerald RC. The human squamous oesophagus has widespread capacity for clonal expansion from cells at diverse stages of differentiation. Gut. 2015;64:11–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Barker N. Epithelial stem cells in the esophagus: who needs them? Cell Stem Cell. 2012;11:284–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Bien-Willner GA, Stankiewicz P, Lupski JR. SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway. Hum Mol Genet. 2007;16:1143–56.PubMedCrossRefGoogle Scholar
  7. 7.
    Bitar KN, Raghavan S, Zakhem E. Tissue engineering in the gut: developments in neuromusculature. Gastroenterology. 2014;146:1614–24.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Boch JA, Shields HM, Antonioli DA, Zwas F, Sawhney RA, Trier JS. Distribution of cytokeratin markers in Barrett’s specialized columnar epithelium. Gastroenterology. 1997;112:760–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Brandt LJ, Blansky RL, Kauvar DR. Repeat laser therapy of recurrent Barrett’s epithelium: success with anacidity. Gastrointest Endosc. 1995;41:267.PubMedCrossRefGoogle Scholar
  10. 10.
    Catry J, Luong-Nguyen M, Arakelian L, Poghosyan T, Bruneval P, Domet T, Michaud L, Sfeir R, Gottrand F, Larghero J, Vanneaux V, Cattan P. Circumferential esophageal replacement by a tissue-engineered substitute using mesenchymal stem cells: an experimental study in mini pigs. Cell Transplant. 2017;26:1831–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen X, Qin R, Liu B, Ma Y, Su Y, Yang CS, Glickman JN, Odze RD, Shaheen NJ. Multilayered epithelium in a rat model and human Barrett’s esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol. 2008;8:1.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chirica M, Veyrie N, Munoz-Bongrand N, Zohar S, Halimi B, Celerier M, Cattan P, Sarfati E. Late morbidity after colon interposition for corrosive esophageal injury: risk factors, management, and outcome. A 20-years’ experience. Ann Surg. 2010;252:271–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Clemons NJ, Wang DH, Croagh D, Tikoo A, Fennell CM, Murone C, Scott AM, Watkins DN, Phillips WA. Sox9 drives columnar differentiation of esophageal squamous epithelium: a possible role in the pathogenesis of Barrett’s esophagus. Am J Physiol Gastrointest Liver Physiol. 2012;303:G1335–46.PubMedCrossRefGoogle Scholar
  14. 14.
    Croagh D, Frede J, Jones PH, Kaur P, Partensky C, Phillips WA. Esophageal stem cells and genetics/epigenetics in esophageal cancer. Ann N Y Acad Sci. 2014;1325:8–14.PubMedCrossRefGoogle Scholar
  15. 15.
    Croagh D, Phillips WA, Redvers R, Thomas RJ, Kaur P. Identification of candidate murine esophageal stem cells using a combination of cell kinetic studies and cell surface markers. Stem Cells. 2007;25:313–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Croagh D, Thomas RJ, Phillips WA, Kaur P. Esophageal stem cells – a review of their identification and characterization. Stem Cell Rev. 2008;4:261–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Daniely Y, Liao G, Dixon D, Linnoila RI, Lori A, Randell SH, Oren M, Jetten AM. Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol. 2004;287:C171–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Diemer P, Markoew S, Le DQ, Qvist N. Poly-epsilon-caprolactone mesh as a scaffold for in vivo tissue engineering in rabbit esophagus. Dis Esophagus. 2015;28:240–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Epperly MW, Shen H, Jefferson M, Greenberger JS. In vitro differentiation capacity of esophageal progenitor cells with capacity for homing and repopulation of the ionizing irradiation-damaged esophagus. In Vivo. 2004;18:675–85.PubMedGoogle Scholar
  20. 20.
    Facompre N, Nakagawa H, Herlyn M, Basu D. Stem-like cells and therapy resistance in squamous cell carcinomas. Adv Pharmacol. 2012;65:235–65.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Fan MR, Gong M, Da LC, Bai L, Li XQ, Chen KF, Li-Ling J, Yang ZM, Xie HQ. Tissue engineered esophagus scaffold constructed with porcine small intestinal submucosa and synthetic polymers. Biomed Mater. 2014;9:015012.PubMedCrossRefGoogle Scholar
  22. 22.
    Fascetti-Leon F, Malerba A, Boldrin L, Leone E, Betalli P, Pasut A, Zanon GF, Gamba PG, Vitiello L, De Coppi P. Murine muscle precursor cells survived and integrated in a cryoinjured gastroesophageal junction. J Surg Res. 2007;143:253–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Forghanifard MM, Taleb S, Abbaszadegan MR. Notch signaling target genes are directly correlated to esophageal squamous cell carcinoma tumorigenesis. Pathol Oncol Res. 2015;21:463–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Frede J, Greulich P, Nagy T, Simons BD, Jones PH. A single dividing cell population with imbalanced fate drives oesophageal tumour growth. Nat Cell Biol. 2016;18:967–78.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gao N, White P, Kaestner KH. Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell. 2009;16:588–99.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ge C, Wu S, Wang W, Liu Z, Zhang J, Wang Z, Li R, Zhang Z, Li Z, Dong S, Wang Y, Xue Y, Yang J, Tan Q, Wang Z, Song X. miR-942 promotes cancer stem cell-like traits in esophageal squamous cell carcinoma through activation of Wnt/beta-catenin signalling pathway. Oncotarget. 2015;6:10964–77.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M. The role of p63 and deltaNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Hum Pathol. 2003;34:850–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Gen Y, Yasui K, Nishikawa T, Yoshikawa T. SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway. Cancer Sci. 2013;104:810–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Goscinski MA, Larsen SG, Giercksky KE, Nesland JM, Suo Z. PDGFR-alpha and CD117 expression pattern in esophageal carcinomas. Anticancer Res. 2015;35:3793–9.PubMedGoogle Scholar
  30. 30.
    Grikscheit T, Ochoa ER, Srinivasan A, Gaissert H, Vacanti JP. Tissue-engineered esophagus: experimental substitution by onlay patch or interposition. J Thorac Cardiovasc Surg. 2003;126:537–44.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Groisman GM, Amar M, Meir A. Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett’s) metaplasia. Mod Pathol. 2004;17:1282–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Guo RJ, Suh ER, Lynch JP. The role of Cdx proteins in intestinal development and cancer. Cancer Biol Ther. 2004;3:593–601.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Hagey DW, Klum S, Kurtsdotter I, Zaouter C, Topcic D, Andersson O, Bergsland M, Muhr J. SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs. PLoS Genet. 2018;14:e1007224.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hall PA, Woodman AC, Campbell SJ, Shepherd NA. Expression of the p53 homologue p63alpha and DeltaNp63alpha in the neoplastic sequence of Barrett’s oesophagus: correlation with morphology and p53 protein. Gut. 2001;49:618–23.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Huo X, Zhang HY, Zhang XI, Lynch JP, Strauch ED, Wang JY, Melton SD, Genta RM, Wang DH, Spechler SJ, Souza RF. Acid and bile salt-induced CDX2 expression differs in esophageal squamous cells from patients with and without Barrett’s esophagus. Gastroenterology. 2010;139:194–203 e191.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Ishida H, Kasajima A, Kamei T, Miura T, Oka N, Yazdani S, Ozawa Y, Fujishima F, Sakurada A, Nakamura Y, Tanaka Y, Kurosumi M, Ishikawa Y, Okada Y, Ohuchi N, Sasano H. SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis. Mod Pathol. 2017;30:660–71.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Jiang M, Ku WY, Zhou Z, Dellon ES, Falk GW, Nakagawa H, Wang ML, Liu K, Wang J, Katzka DA, Peters JH, Lan X, Que J. BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis. J Clin Invest. 2015;125:1557–68.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kalabis J, Oyama K, Okawa T, Nakagawa H, Michaylira CZ, Stairs DB, Figueiredo JL, Mahmood U, Diehl JA, Herlyn M, Rustgi AK. A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J Clin Invest. 2008;118:3860–9.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kano Y, Ishii H, Konno M, Yamasaki M, Miyata H, Nishikawa S, Hamabe A, Ogawa H, Takahashi H, Ohta K, Hasegawa S, Tanaka K, Fukusumi T, Otsuka M, Kawamoto K, Haraguchi N, Fujimoto R, Isobe M, Tomita Y, Matsuura N, Takiguchi S, Mori M, Doki Y. Cells of origin of squamous epithelium, dysplasia and cancer in the head and neck region after bone marrow transplantation. Int J Oncol. 2014a;44:443–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Kano Y, Konno M, Kawamoto K, Tamari K, Hayashi K, Fukusumi T, Satoh T, Tanaka S, Ogawa K, Mori M, Doki Y, Ishii H. Novel drug discovery system for cancer stem cells in human squamous cell carcinoma of the esophagus. Oncol Rep. 2014b;31:1133–8.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Kano Y, Konno M, Ohta K, Haraguchi N, Nishikawa S, Kagawa Y, Hamabe A, Hasegawa S, Ogawa H, Fukusumi T, Noguchi Y, Ozaki M, Kudo T, Sakai D, Satoh T, Ishii M, Mizohata E, Inoue T, Mori M, Doki Y, Ishii H. Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth. Mol Clin Oncol. 2013;1:753–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Kantarcioglu M, Caliskan B, Demirci H, Karacalioglu O, Kekilli M, Polat Z, Gunal A, Akinci M, Uysal C, Eksert S, Gurel H, Celebi G, Avcu F, Ural AU, Bagci S. The efficacy of mesenchymal stem cell transplantation in caustic esophagus injury: an experimental study. Stem Cells Int. 2014;2014:939674.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Katoh M, Katoh M. Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Int J Mol Med. 2006;17:681–5.PubMedGoogle Scholar
  44. 44.
    Kazumori H, Ishihara S, Kinoshita Y. Roles of caudal-related homeobox gene Cdx1 in oesophageal epithelial cells in Barrett’s epithelium development. Gut. 2009;58:620–8.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Keane TJ, DeWard A, Londono R, Saldin LT, Castleton AA, Carey L, Nieponice A, Lagasse E, Badylak SF. Tissue-specific effects of esophageal extracellular matrix. Tissue Eng Part A. 2015;21:2293–300.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Keane TJ, Londono R, Carey RM, Carruthers CA, Reing JE, Dearth CL, D’Amore A, Medberry CJ, Badylak SF. Preparation and characterization of a biologic scaffold from esophageal mucosa. Biomaterials. 2013;34:6729–37.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kong J, Crissey MA, Funakoshi S, Kreindler JL, Lynch JP. Ectopic Cdx2 expression in murine esophagus models an intermediate stage in the emergence of Barrett’s esophagus. PLoS One. 2011;6:e18280.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Koseki J, Matsui H, Konno M, Nishida N, Kawamoto K, Kano Y, Mori M, Doki Y, Ishii H. A trans-omics mathematical analysis reveals novel functions of the ornithine metabolic pathway in cancer stem cells. Sci Rep. 2016;6:20726.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Krishnan K, Komanduri S, Cluley J, Dirisina R, Sinh P, Ko JZ, Li L, Katzman RB, Barrett TA. Radiofrequency ablation for dysplasia in Barrett’s esophagus restores beta-catenin activation within esophageal progenitor cells. Dig Dis Sci. 2012;57:294–302.PubMedCrossRefGoogle Scholar
  50. 50.
    La Francesca S, Aho JM, Barron MR, Blanco EW, Soliman S, Kalenjian L, Hanson AD, Todorova E, Marsh M, Burnette K, DerSimonian H, Odze RD, Wigle DA. Long-term regeneration and remodeling of the pig esophagus after circumferential resection using a retrievable synthetic scaffold carrying autologous cells. Sci Rep. 2018;8:4123.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lee E, Milan A, Urbani L, De Coppi P, Lowdell MW. Decellularized material as scaffolds for tissue engineering studies in long gap esophageal atresia. Expert Opin Biol Ther. 2017;17:573–84.PubMedCrossRefGoogle Scholar
  52. 52.
    Levine DS, Rubin CE, Reid BJ, Haggitt RC. Specialized metaplastic columnar epithelium in Barrett’s esophagus. A comparative transmission electron microscopic study. Lab Investig. 1989;60:418–32.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Li Y, Wo JM, Ellis S, Ray MB, Jones W, Martin RC. Morphological transformation in esophageal submucosa by bone marrow cells: esophageal implantation under external esophageal perfusion. Stem Cells Dev. 2006;15:697–705.PubMedCrossRefGoogle Scholar
  54. 54.
    Liu J, Fan H, Ma Y, Liang D, Huang R, Wang J, Zhou F, Kan Q, Ming L, Li H, Giercksky KE, Nesland JM, Suo Z. Notch1 is a 5-fluorouracil resistant and poor survival marker in human esophagus squamous cell carcinomas. PLoS One. 2013a;8:e56141.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Liu K, Jiang M, Lu Y, Chen H, Sun J, Wu S, Ku WY, Nakagawa H, Kita Y, Natsugoe S, Peters JH, Rustgi A, Onaitis MW, Kiernan A, Chen X, Que J. Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell. 2013b;12:304–15.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Liu K, Lin B, Zhao M, Yang X, Chen M, Gao A, Liu F, Que J, Lan X. The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cell Signal. 2013c;25:1264–71.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Long A, Giroux V, Whelan KA, Hamilton KE, Tetreault MP, Tanaka K, Lee JS, Klein-Szanto AJ, Nakagawa H, Rustgi AK. WNT10A promotes an invasive and self-renewing phenotype in esophageal squamous cell carcinoma. Carcinogenesis. 2015;36:598–606.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Lopez-Lazaro M. Understanding why aspirin prevents cancer and why consuming very hot beverages and foods increases esophageal cancer risk. Controlling the division rates of stem cells is an important strategy to prevent cancer. Oncoscience. 2015;2:849–56.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Lopez-Lazaro M. A local mechanism by which alcohol consumption causes cancer. Oral Oncol. 2016;62:149–52.PubMedCrossRefGoogle Scholar
  60. 60.
    Lord RV, Wickramasinghe K, Johansson JJ, Demeester SR, Brabender J, Demeester TR. Cardiac mucosa in the remnant esophagus after esophagectomy is an acquired epithelium with Barrett’s-like features. Surgery. 2004;136:633–40.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Luc G, Charles G, Gronnier C, Cabau M, Kalisky C, Meulle M, Bareille R, Roques S, Couraud L, Rannou J, Bordenave L, Collet D, Durand M. Decellularized and matured esophageal scaffold for circumferential esophagus replacement: proof of concept in a pig model. Biomaterials. 2018;175:1–18.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Lukaszewicz-Zajac M, Mroczko B, Kozlowski M, Szmitkowski M. Stem cell factor in the serum of patients with esophageal cancer in relation to its histological types. Arch Med Sci. 2017;13:1357–64.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Lynen Jansen P, Klinge U, Anurov M, Titkova S, Mertens PR, Jansen M. Surgical mesh as a scaffold for tissue regeneration in the esophagus. Eur Surg Res. 2004;36:104–11.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Maghsoudlou P, Ditchfield D, Klepacka DH, Shangaris P, Urbani L, Loukogeorgakis SP, Eaton S, De Coppi P. Isolation of esophageal stem cells with potential for therapy. Pediatr Surg Int. 2014;30:1249–56.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Malvasio V, Ainoedhofer H, Ackbar R, Hoellwarth ME, Saxena AK. Effects of sodium hydroxide exposure on esophageal epithelial cells in an in vitro ovine model: implications for esophagus tissue engineering. J Pediatr Surg. 2012;47:874–80.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Marchetti M, Caliot E, Pringault E. Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes. J Cell Sci. 2003;116:1429–36.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Mazzanti B, Lorenzi B, Lorenzoni P, Borghini A, Boieri M, Lorenzi M, Santosuosso M, Bosi A, Saccardi R, Weber E, Pessina F. Treatment of experimental esophagogastric myotomy with bone marrow mesenchymal stem cells in a rat model. Neurogastroenterol Motil. 2013;25:e669–79.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Menke V, van Es JH, de Lau W, van den Born M, Kuipers EJ, Siersema PD, de Bruin RW, Kusters JG, Clevers H. Conversion of metaplastic Barrett’s epithelium into post-mitotic goblet cells by gamma-secretase inhibition. Dis Model Mech. 2010;3:104–10.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Mizushima T, Ohnishi S, Hosono H, Yamahara K, Tsuda M, Shimizu Y, Kato M, Asaka M, Sakamoto N. Oral administration of conditioned medium obtained from mesenchymal stem cell culture prevents subsequent stricture formation after esophageal submucosal dissection in pigs. Gastrointest Endosc. 2017;86:542–552 e541.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Moghbeli M, Moghbeli F, Forghanifard MM, Abbaszadegan MR. Cancer stem cell detection and isolation. Med Oncol. 2014;31:69.PubMedCrossRefGoogle Scholar
  71. 71.
    Moons LM, Bax DA, Kuipers EJ, Van Dekken H, Haringsma J, Van Vliet AH, Siersema PD, Kusters JG. The homeodomain protein CDX2 is an early marker of Barrett’s oesophagus. J Clin Pathol. 2004;57:1063–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K. Cdx1 induced intestinal metaplasia in the transgenic mouse stomach: comparative study with Cdx2 transgenic mice. Gut. 2004;53:1416–23.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Nayal B, Vasudevan G, Rao AC, Kudva R, Valliathan M, Mathew M, Rao L. Primary small cell carcinoma of the esophagus – an eight year retrospective study. J Clin Diagn Res. 2015;9:EC04–6.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Nicholson AM, Graham TA, Simpson A, Humphries A, Burch N, Rodriguez-Justo M, Novelli M, Harrison R, Wright NA, McDonald SA, Jankowski JA. Barrett’s metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut. 2012;61:1380–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Nieponice A, Ciotola FF, Nachman F, Jobe BA, Hoppo T, Londono R, Badylak S, Badaloni AE. Patch esophagoplasty: esophageal reconstruction using biologic scaffolds. Ann Thorac Surg. 2014;97:283–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Nieponice A, Gilbert TW, Johnson SA, Turner NJ, Badylak SF. Bone marrow-derived cells participate in the long-term remodeling in a mouse model of esophageal reconstruction. J Surg Res. 2013;182:e1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Niu Y, Shen H, Epperly M, Zhang X, Nie S, Cao S, Greenberger JS. Protection of esophageal multi-lineage progenitors of squamous epithelium (stem cells) from ionizing irradiation by manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) gene therapy. In Vivo. 2005;19:965–74.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Ohki T, Yamato M, Okano T, Yamamoto M. Regenerative medicine: tissue-engineered cell sheet for the prevention of post-esophageal ESD stricture. Gastrointest Endosc Clin N Am. 2014;24:273–81.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Ohki T, Yamato M, Ota M, Takagi R, Murakami D, Kondo M, Sasaki R, Namiki H, Okano T, Yamamoto M. Prevention of esophageal stricture after endoscopic submucosal dissection using tissue-engineered cell sheets. Gastroenterology. 2012;143:582–588 e582.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Okumura T, Shimada Y, Imamura M, Yasumoto S. Neurotrophin receptor p75(NTR) characterizes human esophageal keratinocyte stem cells in vitro. Oncogene. 2003;22:4017–26.PubMedCrossRefGoogle Scholar
  81. 81.
    Park SY, Choi JW, Park JK, Song EH, Park SA, Kim YS, Shin YS, Kim CH. Tissue-engineered artificial oesophagus patch using three-dimensionally printed polycaprolactone with mesenchymal stem cells: a preliminary report. Interact Cardiovasc Thorac Surg. 2016;22:712–7.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Perin S, McCann CJ, Borrelli O, De Coppi P, Thapar N. Update on foregut molecular embryology and role of regenerative medicine therapies. Front Pediatr. 2017;5:91.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Phillips RW, Frierson HF Jr, Moskaluk CA. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am J Surg Pathol. 2003;27:1442–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Piazzolla D, Palla AR, Pantoja C, Canamero M, de Castro IP, Ortega S, Gomez-Lopez G, Dominguez O, Megias D, Roncador G, Luque-Garcia JL, Fernandez-Tresguerres B, Fernandez AF, Fraga MF, Rodriguez-Justo M, Manzanares M, Sanchez-Carbayo M, Garcia-Pedrero JM, Rodrigo JP, Malumbres M, Serrano M. Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia. Nat Commun. 2014;5:4226.PubMedCrossRefGoogle Scholar
  85. 85.
    Poghosyan T, Catry J, Luong-Nguyen M, Bruneval P, Domet T, Arakelian L, Sfeir R, Michaud L, Vanneaux V, Gottrand F, Larghero J, Cattan P. Esophageal tissue engineering: current status and perspectives. J Visc Surg. 2016;153:21–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Poghosyan T, Gaujoux S, Vanneaux V, Bruneval P, Domet T, Lecourt S, Jarraya M, Sfeir R, Larghero J, Cattan P. In vitro development and characterization of a tissue-engineered conduit resembling esophageal wall using human and pig skeletal myoblast, oral epithelial cells, and biologic scaffolds. Tissue Eng Part A. 2013;19:2242–52.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Que J, Okubo T, Goldenring JR, Nam KT, Kurotani R, Morrisey EE, Taranova O, Pevny LH, Hogan BL. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development. 2007;134:2521–31.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Raghoebir L, Bakker ER, Mills JC, Swagemakers S, Kempen MB, Munck AB, Driegen S, Meijer D, Grosveld F, Tibboel D, Smits R, Rottier RJ. SOX2 redirects the developmental fate of the intestinal epithelium toward a premature gastric phenotype. J Mol Cell Biol. 2012;4:377–85.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Rassouli FB, Matin MM, Bahrami AR, Ghaffarzadegan K, Cheshomi H, Lari S, Memar B, Kan MS. Evaluating stem and cancerous biomarkers in CD15+CD44+ KYSE30 cells. Tumour Biol. 2013;34:2909–20.PubMedCrossRefGoogle Scholar
  90. 90.
    Rassouli FB, Matin MM, Bahrami AR, Ghaffarzadegan K, Sisakhtnezhad S, Cheshomi H, Abbasi F. SOX2 expression in gastrointestinal cancers of Iranian patients. Int J Biol Markers. 2015;30:e315–20.PubMedCrossRefGoogle Scholar
  91. 91.
    Reinardy HC, Emerson CE, Manley JM, Bodnar AG. Tissue regeneration and biomineralization in sea urchins: role of Notch signaling and presence of stem cell markers. PLoS One. 2015;10:e0133860.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Roman S, Petre A, Thepot A, Hautefeuille A, Scoazec JY, Mion F, Hainaut P. Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol. 2007;293:G45–53.PubMedCrossRefGoogle Scholar
  93. 93.
    Rosekrans SL, Baan B, Muncan V, van den Brink GR. Esophageal development and epithelial homeostasis. Am J Physiol Gastrointest Liver Physiol. 2015a;309:G216–28.PubMedCrossRefGoogle Scholar
  94. 94.
    Rosekrans SL, Heijmans J, Buller NV, Westerlund J, Lee AS, Muncan V, van den Brink GR. ER stress induces epithelial differentiation in the mouse oesophagus. Gut. 2015b;64:195–202.PubMedCrossRefGoogle Scholar
  95. 95.
    Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, Van Houdt WJ, Pronk A, Van Gorp J, Siersema PD, Clevers H. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762–72.PubMedCrossRefGoogle Scholar
  96. 96.
    Satoh K, Mutoh H, Eda A, Yanaka I, Osawa H, Honda S, Kawata H, Kihira K, Sugano K. Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori. Helicobacter. 2002;7:192–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Sawhney RA, Shields HM, Allan CH, Boch JA, Trier JS, Antonioli DA. Morphological characterization of the squamocolumnar junction of the esophagus in patients with and without Barrett’s epithelium. Dig Dis Sci. 1996;41:1088–98.PubMedCrossRefGoogle Scholar
  98. 98.
    Shoreibah MG, Jackson CL, Price PW, Meagher R, Godwin AK, Cai Q, Gildersleeve JC. Anti-human embryonic stem cell monoclonal antibody Hesca-2 binds to a glycan epitope commonly found on carcinomas. Stem Cells Dev. 2011;20:515–25.PubMedCrossRefGoogle Scholar
  99. 99.
    Sjoqvist S, Jungebluth P, Lim ML, Haag JC, Gustafsson Y, Lemon G, Baiguera S, Burguillos MA, Del Gaudio C, Rodriguez AB, Sotnichenko A, Kublickiene K, Ullman H, Kielstein H, Damberg P, Bianco A, Heuchel R, Zhao Y, Ribatti D, Ibarra C, Joseph B, Taylor DA, Macchiarini P. Experimental orthotopic transplantation of a tissue-engineered oesophagus in rats. Nat Commun. 2014;5:3562.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Soliman S, Laurent J, Kalenjian L, Burnette K, Hedberg B, La Francesca S. A multilayer scaffold design with spatial arrangement of cells to modulate esophageal tissue growth. J Biomed Mater Res B Appl Biomater. 2018;107:324–31.PubMedCrossRefGoogle Scholar
  101. 101.
    Spechler SJ, Souza RF. Stem cells in Barrett’s esophagus: HALOs or horns? Gastrointest Endosc. 2008;68:41–3.PubMedCrossRefGoogle Scholar
  102. 102.
    Spurrier RG, Speer AL, Hou X, El-Nachef WN, Grikscheit TC. Murine and human tissue-engineered esophagus form from sufficient stem/progenitor cells and do not require microdesigned biomaterials. Tissue Eng Part A. 2015;21:906–15.PubMedCrossRefGoogle Scholar
  103. 103.
    Takubo K, Fujita M, Izumiyama N, Nakamura K, Ishikawa N, Poon SS, Fujiwara M, Sawabe M, Matsuura M, Grabsch H, Arai T, Aida J. Q-FISH analysis of telomere and chromosome instability in the oesophagus with and without squamous cell carcinoma in situ. J Pathol. 2010;221:201–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Tan B, Wei RQ, Tan MY, Luo JC, Deng L, Chen XH, Hou JL, Li XQ, Yang ZM, Xie HQ. Tissue engineered esophagus by mesenchymal stem cell seeding for esophageal repair in a canine model. J Surg Res. 2013;182:40–8.PubMedCrossRefGoogle Scholar
  105. 105.
    Taniguchi H, Moriya C, Igarashi H, Saitoh A, Yamamoto H, Adachi Y, Imai K. Cancer stem cells in human gastrointestinal cancer. Cancer Sci. 2016;107:1556–62.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Taylor C, Loomans HA, Le Bras GF, Koumangoye RB, Romero-Morales AI, Quast LL, Zaika AI, El-Rifai W, Andl T, Andl CD. Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma. Oncotarget. 2015;6:34228–44.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Tevlin R, Atashroo D, Duscher D, Mc Ardle A, Gurtner GC, Wan DC, Longaker MT. Impact of surgical innovation on tissue repair in the surgical patient. Br J Surg. 2015;102:e41–55.PubMedCrossRefGoogle Scholar
  108. 108.
    Tomita H, Tanaka K, Tanaka T, Hara A. Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 2016;7:11018–32.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Vaiphei K, Sinha SK, Kochhar R. Comparative analysis of Oct4 in different histological subtypes of esophageal squamous cell carcinomas in different clinical conditions. Asian Pac J Cancer Prev. 2014;15:3519–24.PubMedCrossRefGoogle Scholar
  110. 110.
    van der Sluis M, Vincent A, Bouma J, Korteland-Van Male A, van Goudoever JB, Renes IB, Van Seuningen I. Forkhead box transcription factors Foxa1 and Foxa2 are important regulators of Muc2 mucin expression in intestinal epithelial cells. Biochem Biophys Res Commun. 2008;369:1108–13.PubMedCrossRefGoogle Scholar
  111. 111.
    von Furstenberg RJ, Li J, Stolarchuk C, Feder R, Campbell A, Kruger L, Gonzalez LM, Blikslager AT, Cardona DM, McCall SJ, Henning SJ, Garman KS. Porcine esophageal submucosal gland culture model shows capacity for proliferation and differentiation. Cell Mol Gastroenterol Hepatol. 2017;4:385–404.CrossRefGoogle Scholar
  112. 112.
    Wang DH, Clemons NJ, Miyashita T, Dupuy AJ, Zhang W, Szczepny A, Corcoran-Schwartz IM, Wilburn DL, Montgomery EA, Wang JS, Jenkins NA, Copeland NA, Harmon JW, Phillips WA, Watkins DN. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett’s metaplasia. Gastroenterology. 2010;138:1810–22.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wang DH, Souza RF. Transcommitment: paving the way to Barrett’s metaplasia. Adv Exp Med Biol. 2016;908:183–212.PubMedCrossRefGoogle Scholar
  114. 114.
    Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J Clin Invest. 2014;124:3767–80.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Wang F, Maeda Y, Zachar V, Ansari T, Emmersen J. Regeneration of the oesophageal muscle layer from oesophagus acellular matrix scaffold using adipose-derived stem cells. Biochem Biophys Res Commun. 2018;503:271–7.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Wong NA, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, Maynard N, Marshall R, Bodmer WF. CDX1 is an important molecular mediator of Barrett’s metaplasia. Proc Natl Acad Sci U S A. 2005;102:7565–70.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Workman MJ, Mahe MM, Trisno S, Poling HM, Watson CL, Sundaram N, Chang CF, Schiesser J, Aubert P, Stanley EG, Elefanty AG, Miyaoka Y, Mandegar MA, Conklin BR, Neunlist M, Brugmann SA, Helmrath MA, Wells JM. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med. 2017;23:49–59.PubMedCrossRefGoogle Scholar
  118. 118.
    Wroblewski LE, Peek RM Jr, Coburn LA. The role of the microbiome in gastrointestinal cancer. Gastroenterol Clin N Am. 2016;45:543–56.CrossRefGoogle Scholar
  119. 119.
    Xu M, Luo J. Alcohol and cancer stem cells. Cancers (Basel). 2017;9:158.CrossRefGoogle Scholar
  120. 120.
    Zhang C, Zhang Y, Feng Z, Zhang F, Liu Z, Sun X, Ruan M, Liu M, Jin S. Therapeutic effect of dental pulp stem cell transplantation on a rat model of radioactivity-induced esophageal injury. Cell Death Dis. 2018;9:738.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Zhang X, Lu F, Wang J, Yin F, Xu Z, Qi D, Wu X, Cao Y, Liang W, Liu Y, Sun H, Ye T, Zhang H. Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells. Cell Rep. 2013;5:445–57.PubMedCrossRefGoogle Scholar
  122. 122.
    Zhang Y, Jiang M, Kim E, Lin S, Liu K, Lan X, Que J. Development and stem cells of the esophagus. Semin Cell Dev Biol. 2017;66:25–35.PubMedCrossRefGoogle Scholar
  123. 123.
    Zhong B, Wang T, Lun X, Zhang J, Zheng S, Yang W, Li W, Xiang AP, Chen Z. Contribution of nestin positive esophageal squamous cancer cells on malignant proliferation, apoptosis, and poor prognosis. Cancer Cell Int. 2014;14:57.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zhuang ZH, Tsao SW, Deng W, Wang JD, Xia HH, He H, Feng HC, Wang LD, Gu Q, Lam SK, Lin MC, Kung HF, Wong BC. Early upregulation of cyclooxygenase-2 in human papillomavirus type 16 and telomerase-induced immortalization of human esophageal epithelial cells. J Gastroenterol Hepatol. 2008;23:1613–20.PubMedCrossRefGoogle Scholar
  125. 125.
    Zhuravleva M, Gilazieva Z, Grigoriev TE, Shepelev AD, Kh Tenchurin T, Kamyshinsky R, Krasheninnikov SV, Orlov S, Caralogli G, Archipova S, Holterman MJ, Mavlikeev M, Deev RV, Chvalun SN, Macchiarini P. In vitro assessment of electrospun polyamide-6 scaffolds for esophageal tissue engineering. J Biomed Mater Res B Appl Biomater. 2018;107:253–68.PubMedCrossRefGoogle Scholar
  126. 126.
    Zinovyeva MV, Monastyrskaya GS, Kopantzev EP, Vinogradova TV, Kostina MB, Sass AV, Filyukova OB, Uspenskaya NY, Sukhikh GT, Sverdlov ED. Identification of some human genes oppositely regulated during esophageal squamous cell carcinoma formation and human embryonic esophagus development. Dis Esophagus. 2010;23:260–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Maximos Frountzas
    • 1
  • Dimitrios Schizas
    • 1
  • Alkistis Kapelouzou
    • 2
  • Theodoros Liakakos
    • 1
  1. 1.First Department of Surgery, Laikon General Hospital, School of MedicineNational and Kapodistrian University of AthensAthensGreece
  2. 2.Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of AthensAthensGreece

Personalised recommendations