title: GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer.
abstract: Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived "colonosphere" cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis, and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multilineage differentiation, proliferation, and tumor growth without reducing the tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively correlated with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity, but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity.
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Emmink
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jamila
authors.initials: J
authors.lastname: Laoukili
authors.affiliation: Department Biochemistry of Micronutrients Department, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Kipp
authors.affiliation: Department of Oncogenomics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Klaas M
authors.initials: KM
authors.lastname: Govaert
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Fatrai
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Andre
authors.initials: A
authors.lastname: Verheem
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.affiliation: Department Biochemistry of Micronutrients Department, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Brigelius-Flohé
authors.affiliation: Oncoproteomics Laboratory, Department of Medical Oncology, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Jimenez
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
authors.affiliation: Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands. o.kranenburg@umcutrecht.nl.
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005979:Glutathione Peroxidase / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D054481:Thioredoxin Reductase 1 / Q000502:physiology
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C117436:GPX2 protein, human; D005979:Glutathione Peroxidase; D054481:Thioredoxin Reductase 1