Figure 19.

Oxidative stress drives tissue cancerization: The field effect. In the field effect, it is believed that both the malignant tumor cells and the surrounding or adjacent normal area have undergone a mysterious “cancerization” process to allow for the development of multiple independent foci of tumor growth in a given area. Both genetic and epigenetic alterations have been invoked to explain the field effect, but it still remains an enigma. Here, we suggest that the field effect could be mediated and propagated by oxidative (ROS) and nitrative (NO) stress in cancer associated fibroblasts. First, we envision that cancer cells could induce oxidative stress in adjacent fibroblasts. Then, oxidative stress in the adjacent fibroblasts could be laterally propagated from cell-to-cell like a virus, resulting in the amplification of oxidative stress in a given tissue area or field. This would then provide a “mutagenic/oxidative field” resulting in widespread ROS production and DNA damage. In support of these ideas, here we show that bystander oxidative stress is sufficient to induce DNA damage and aneuploidy in co-cultured MCF7 cells. Furthermore, we demonstrate that eNOS-expressing fibroblasts (undergoing oxidative and nitrative stress) have the ability to induce the downregulation of Cav-1 in adjacent normal fibroblasts, when they are co-cultured together. Thus, oxidative and/or nitrative stress in cancer associated fibroblasts provides a new paradigm by which we can understand how “field cancerization” occurs, and how it can be passed from cell-to-cell in a “contagious” fashion, essentially propagated as “waves of oncogenic stress”.