Data from GPx2 Suppression of H<sub>2</sub>O<sub>2</sub> Stress Links the Formation of Differentiated Tumor Mass to Metastatic Capacity in Colorectal Cancer

Abstract

<div>Abstract<p>Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H<sub>2</sub>O<sub>2</sub>-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H<sub>2</sub>O<sub>2</sub> stress and differentiation in patient-derived “colonosphere” cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H<sub>2</sub>O<sub>2</sub>-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 H<sub>2</sub>O<sub>2</sub>-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 H<sub>2</sub>O<sub>2</sub> 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. <i>Cancer Res; 74(22); 6717–30. ©2014 AACR</i>.</p></div>