Out of touch: Signaling by cell adhesions in diffuse-type gastric cancer

Abstract

Epithelial cells in our body protect underlying tissues from harmful external factors. E-cadherin is an important protein that connects epithelial cells to each other. When E-cadherin does not function properly, diseases such as cancer can develop, in which cells divide uncontrollably and damage tissues as they spread. People at higher risk for diffuse-type gastric cancer (DGC) carry an inherited DNA error (mutation) that causes E-cadherin to function poorly. In the stomachs of these individuals, epithelial cells often move outside the epithelial layer into the underlying tissue. Initially, these cells are harmless because they divide very little. Over time, however, they can transform into cancer cells. It is difficult to predict if and when cancer will develop. For this reason, patients often choose to have their stomach removed preventively. If we can understand how cells leave the epithelial layer and how harmless cells develop into cancer, it may become possible in the future to avoid such drastic surgeries. The research presented in this thesis shows that loss of E-cadherin disrupts cell division, causing cells to end up in the wrong location within the tissue. We also identified additional mutations that may contribute to cancer development, as well as adaptations in both cancer cells and surrounding tissue that allow the cells to continue receiving signals to divide. We hope that these findings will eventually help predict if and when gastric cancer will develop, and contribute to the development of new treatments targeting the mechanisms involved in the progression of DGC.