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131. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

25.03. - 28.03.2014, Berlin

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Aspirin targeting stem like side population cells in human esophageal cancer cells and its effect on chemoresistance

Meeting Abstract

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  • Yue Zhao - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Yan Wang - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Bettina Schwarz - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Lu Zhao - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Anneli Tichmacher - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Josef Mysliwietz - Helmholtz Center for Environment and Health, Institute of Molecular Immunology, München
  • Joachim Ellwart - Helmholtz Center for Environment and Health, Institute of Molecular Immunology, München
  • Qi Bao - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Hanno Nieß - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Dominik Modest - LMU München - Klinikum Großhadern, Department of Medicine III, München
  • Peter Camaj - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Martin K. Angele - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Karl-Walter Jauch - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München
  • Peter Nelson - LMU München - Klinikum Innerstadt, Clinical Biochemistry Group, Medizinische Klinik und Policlinic IV, München
  • Christiane J. Bruns - LMU München - Klinikum Großhadern, Chirurgische Klinik und Poliklinik-Forschung Chirurgie, München

Deutsche Gesellschaft für Chirurgie. 131. Kongress der Deutschen Gesellschaft für Chirurgie. Berlin, 25.-28.03.2014. Düsseldorf: German Medical Science GMS Publishing House; 2014. Doc14dgch352

doi: 10.3205/14dgch352, urn:nbn:de:0183-14dgch3524

Published: March 21, 2014

© 2014 Zhao et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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Introduction: Taking aspirin was reported to prevent the development of both esophageal squamous cell cancer and adenocarcinoma. Some researchers indicated that aspirin could induce tumor cells apoptosis and might modulate cancer stem cells regulation through the Wnt/beta-catenin pathway. Previous results have shown that side population (SP) cells in esophageal cancer cell lines have stem cell-like properties and may be responsible for therapy resistance. Our objective was to determine whether aspirin by targeting Wnt signaling affects the biological properties of side population cells in esophageal cancer and its therapeutic effects both in vitro and in vivo.

Material and methods: After treatment with aspirin, Hoechst 33342 staining was used to define the proportion of SP cells in three human esophageal cancer cell lines (OE19, OE21 and OE33) together with a detection of ABCG2 expression. SP and non-SP cells in OE19 were isolated by flow cytometric sorting and further treated with aspirin. Wnt signalling was activated in the 5-FU resistant variant of OE19. The expression of Wnt signaling targets with and without aspirin treatment was further evaluated by PCR array. The effect of aspirin on the expression of the 5-FU resistant marker thymidylate synthase, mesenchymal cell marker vimentin and some wnt-associated genes were detected by western blot. The efficacy of aspirin alone and in combination with 5-FU and Cisplatin administration by intraperitoneal injection regarding OE19 tumorigenicity was evaluated in a subcutaneous xenograft model.

Results: In OE19, SP cells were dramatically decreased from the percentage of 19.7±1.0 to 6.9±1.0, 3.4±0.9, and 1.8±0.4 (p<0.001) after 24h, 48h, and 72h incubation with 5mM aspirin, respectively. Similar results were observed in OE21 and OE33. In particular, aspirin displayed a markedly stronger effect on SP as compared to non-SP cell proliferation together with a significant reduction of the ABCG2+ subpopulation. Wnt signalling targets-SOX2, BMP4, COX-2, Cyclin D1, and CD44 displayed a significant downregulation in OE19 5-FU resistant cells following aspirin inhibition (> 2 fold change). TS and vimentin were significantly decreased after aspirin treatment alone or combined with 5-FU or Cisplatin. In addition, 5-FU and Cisplatin administration with daily aspirin severely impaired tumor weight comparing to chemotherapy alone (0.14±0.11g vs 0.75±0.2g, p=0.0004), which is associated to a decrease of the SP content in primary tumors.

Conclusion: Aspirin may affect esophageal cancer by targeting side population cells through the wnt signaling pathway. This finding indicates a promising therapeutic strategy considering aspirin or other NSAIDs as additional therapy against esophageal cancer.