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Induction of tumor stem cell differentiation—novel strategy to overcome therapy resistance in gastric cancer

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Abstract

Purpose

Metastases are a frequent finding in gastric cancer and are associated with poor prognosis. A recently discovered link between metabolic changes, differentiation, and therapy resistance due to tumor stem cells could depict a novel approach in cancer research and therapy. Phosphoglycerate kinase 1 (PGK1) is a metabolic enzyme and is known to be involved in enabling gastric cancer cells to be invasive and to disseminate. In this study, we investigated if PGK1 is a promising candidate in inducing stem cell differentiation in gastric cancer.

Materials and methods

MKN45 gastric cancer cells were used due to their known cancer stem cell population, which is defined by the surface marker CD44. MKN45 cells were separated between CD44+ and CD44− cells and, in equal parts, incubated with shRNA anti-PGK1 using fluorescence-activated cell sorting (FACS) analysis; they were then injected into nude mice to evaluate their tumor growth behavior in vivo. Further, the invasive potential of gastric cancer cells was evaluated in vitro using the xCelligence analyzing system.

Results

CD44+ gastric cancer cells treated with and without shRNA anti-PGK1 were capable to cause tumor growth in vivo, whereas tumor growth in CD44+ cells treated with shRNA anti-PGK1 was considerably smaller in comparison with that in CD44+ cells without treatment. CD44− cells did not show any noticeable tumor growth in vivo. By targeting PGK1, the invasive potential of gastric cancer cells was impressively reduced in vitro. In all our cells, which were targeted with shRNA anti-PGK1, we did not find any change that is in accordance with the phenotype of the cells using FACS analysis.

Conclusions

Our findings suggest that targeting the key metabolic enzyme PGK1 in gastric cancer cells may open a new chapter in cancer treatment, which is well worth for further exploration in combination with recent chemotherapy, and might be a promising possibility to overcome therapy resistance in gastric cancer.

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Acknowledgments

We thank Dr. Bühring und Ms. Treml for their kindness in providing the FACS analysis system and their help in supporting our study.

Conflicts of interest

This manuscript contains original material that has not been published or submitted to any other journal. The authors declare no competing conflict of interest.

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Authors and Affiliations

  1. Department of General and Transplant Surgery and Comprehensive Cancer Center, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany

    Derek Zieker, Sarah Bühler, Zeynep Üstündag, Ingmar Königsrainer, Sebastian Manncke, Khaled Bajaeifer, Alfred Königsrainer & Jörg Glatzle

  2. Department of Transfusion Medicine, University of Tuebingen, Tuebingen, Germany

    Sarah Bühler, Zeynep Üstündag & Hinnak Northoff

  3. Department of Pathology, University of Tuebingen, Tuebingen, Germany

    Jörg Vollmer & Falko Fend

Authors
  1. Derek Zieker
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  2. Sarah Bühler
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  3. Zeynep Üstündag
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  5. Sebastian Manncke
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  8. Falko Fend
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  9. Hinnak Northoff
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  10. Alfred Königsrainer
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  11. Jörg Glatzle
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Correspondence to Derek Zieker.

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Zieker, D., Bühler, S., Üstündag, Z. et al. Induction of tumor stem cell differentiation—novel strategy to overcome therapy resistance in gastric cancer. Langenbecks Arch Surg 398, 603–608 (2013). https://doi.org/10.1007/s00423-013-1058-5

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  • DOI: https://doi.org/10.1007/s00423-013-1058-5

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