Loss of p53 in stromal fibroblasts promotes epithelial cell invasion through redox-mediated ICAM1 signal

Abstract

Tumor microenvironment plays a major role in cancer development. Understanding how the stroma affects epithelial transformation will provide a basis for new preventive strategies. Recent evidence suggests that oxidative stress in stroma may play a role in cancer progression, and loss of p53 function in the stromal cells was associated with poor prognosis and high tumor recurrence. However, the underlying mechanisms remain poorly understood. Here, we investigated the role of p53 loss in fibroblasts in epithelial transformation and the mechanistic involvement of reactive species. Using 3D organotypic culture and other assays, we report that the stroma containing p53-deficient fibroblasts could induce the nontumorigenic epithelial cells of oral and ovarian tissue origins to become invasive through reactive nitrogen species (RNS)-mediated release of the cytokine ICAM1. The p53-deficient fibroblasts have increased RNS production and accumulation of oxidative DNA-damage products associated with specific upregulation of endothelial nitric oxide synthase (eNOS). Suppression of RNS production by siRNA of eNOS or the antioxidant NAC reduced ICAM1 expression and prevented the stroma-mediated epithelial invasion. Our study uncovers the novel mechanism by which redox alteration associated with loss of p53 in stromal fibroblasts functions as a key inducer of epithelial transformation and invasion via RNS-mediated ICAM1 signaling. Thus, the modulation of redox signaling in the microenvironment may serve as a new approach to preventing epithelial transformation and suppressing cancer invasion.