GPx2 suppression of H2O2 stress links the formation of differentiated tumor mass to metastatic capacity in colorectal cancer.

Benjamin L Emmink,Anna P Kipp,Onno Kranenburg,Ernst J.A Steller,Andre Verheem,Szabolcs Fatrai,Klaas M Govaert,Jamila Laoukili,Connie R Jimenez,Jan Koster,Regina Brigelius-Flohé,Inne H.M Borel Rinkes

doi:10.1158/0008-5472.can-14-1645

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.

Highlights

Oxidative stress due to accumulation of reactive oxygen species (ROS) such as superoxide or hydrogen peroxide is commonly observed in many types of cancer cells [1,2,3]
We show that glutathione peroxidase 2 (GPx2) regulates two aspects of colon tumor growth
It is required for the survival of clonogenic tumor cells in response to H2O2 stress

Summary

Introduction

Oxidative stress due to accumulation of reactive oxygen species (ROS) such as superoxide or hydrogen peroxide is commonly observed in many types of cancer cells [1,2,3]. Several parameters of oxidative stress, such as lipid peroxidation and DNA hydroxylation, are increased with increasing stage [4,5,6]. Specific ROS, like H2O2, can act as second messengers in protumorigenic signaling pathways. ROS generation is required for the expansion of intestinal stem cells during tumor initiation in. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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