Early Transformative Changes in Normal Ovarian Surface Epithelium Induced by Oxidative Stress Require Akt Upregulation, DNA Damage, and Epithelial-Stromal Interaction
Menée in vitro à l'aide d'un modèle tridimensionnel, cette étude met en évidence un mécanisme par lequel, sous l'action d'un stress oxydant, l'activation de la signalisation Akt induit la transformation des cellules épithéliales de la surface de l'ovaire
Ovarian cancer is the deadliest gynecological malignancy due to detection at a late stage when the disease has metastasized. One likely progenitor cell type of ovarian cancer is the ovarian surface epithelium (OSE), which proliferates rapidly in the presence of inflammatory cytokines and oxidative stress following ovulation. To determine whether oxidative stress induces DNA damage leading to spontaneous transformative changes in normal OSE, an immortalized mouse OSE cell line (MOSE cells) or normal mouse ovarian organoids were treated with hydrogen peroxide and loss of contact inhibition was assessed by soft agar assay. In response to hydrogen peroxide, OSE cells grown in 3D exhibited growth in soft agar but MOSE cells grown on 2D plastic did not, indicating a critical role for epithelial-stromal interactions in neoplastic initiation. Loss of contact inhibition in response to hydrogen peroxide correlated with an increase in proliferation, DNA damage, and upregulation of the oncogene Akt1. Use of a reactive oxygen species scavenger or Akt inhibitor blocked hydrogen peroxide-induced proliferation and growth in soft agar. Although parental MOSE cells did not undergo transformation by hydrogen peroxide, MOSE cells stably overexpressing constitutively active myristoylated Akt or knockdown of PTEN exhibited loss of contact inhibition and increased proliferation. This study indicates that normal OSE undergo transformative changes induced by oxidative stress and that this process requires Akt upregulation and activation. A 3D model that retains tissue architecture is critical for studying this process and may lead to development of new intervention strategies directed at early stages of ovarian cancer.
http://carcin.oxfordjournals.org/content/early/2013/01/07/carcin.bgt003.abstract