title: Induction of tumor stem cell differentiation--novel strategy to overcome therapy resistance in gastric cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Department of General and Transplant Surgery and Comprehensive Cancer Center, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany. derek.zieker@med.uni-tuebingen.de
authors: Derek
authors: D
authors: Zieker
authors: Sarah
authors: S
authors: Bühler
authors: Zeynep
authors: Z
authors: Ustündag
authors: Ingmar
authors: I
authors: Königsrainer
authors: Sebastian
authors: S
authors: Manncke
authors: Khaled
authors: K
authors: Bajaeifer
authors: Jörg
authors: J
authors: Vollmer
authors: Falko
authors: F
authors: Fend
authors: Hinnak
authors: H
authors: Northoff
authors: Alfred
authors: A
authors: Königsrainer
authors: Jörg
authors: J
authors: Glatzle
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010735:Phosphoglycerate Kinase / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000503:physiopathology* / Q000628:therapy*; D014183:Transplantation, Heterologous
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C577282:PGK1 protein, human; D010735:Phosphoglycerate Kinase