Entosis: it's a cell-eat-cell world

Abstract

In this issue, Overholtzer et al. (2007) describe a new nonapoptotic cell death pathway termed "entosis" in mammary epithelial cells that have detached from the extracellular matrix (ECM). Given that surviving detachment from the ECM is an event associated with the progression of epithelial cancers, entosis--along with apoptosis--may contribute to tumor suppression by promoting the elimination of cancer cells.

Figure 1. Regulation of Cell Death in Mammary Acinar Cells

Three-dimensional mammary ductal morphogenesis modeled in vitro leads to multicellular spheroid acinar formation in the presence of an extracellular matrix (ECM). Cells at the external rim of the acinus form tight and adherens junctions (TJ and AJ, respectively) and establish a polarized epithelial layer surrounded by a basement membrane, an organizational state that maintains survival signaling in these cells (Nelson and Bissell, 2006). The central acinar cells are subjected to stresses and are eliminated by several different mechanisms, generating a hollow lumen. The stress of cell detachment and the loss of survival signaling by integrins activate a form of cell death by apoptosis termed anoikis, resulting in lumen formation (Debnath et al., 2002; Nelson and Bissell, 2006). The central acinar cells are also subjected to metabolic stress induced by hypoxia and likely also nutrient deprivation that initiates the catabolic cellular self-eating process of autophagy to recycle intracellular nutrients to support survival (Karantza-Wadsworth et al., 2007). Autophagy can enable long-term survival of apoptosis-defective central acinar cells facilitating luminal filling. Inhibiting autophagy (and thereby nutrient recycling) in metabolically stressed, apoptosis-defective central acinar cells results in necrotic cell death (Karantza-Wadsworth et al., 2007). ECM detachment of central acinar cells and adherens junction formation can also lead to cell invasion and lysosome-mediated degradation and cell death of the invading cell by the process of entosis (Overholtzer et al., 2007). The failure to eliminate luminal cells can be one factor that contributes to filling of the lumen, which is a step in the progression of epithelial cancers.