Detachment-induced autophagy duringanoikisand lumen formation in epithelial acini

Abstract

The individual units (called acini) comprising glandular epithelium possess a hollow lumen that is filled in early epithelial cancers. While investigating the generation of this hollow lumen using an in vitro three-dimensional (3D) epithelial cell culture model, we observed extensive autophagy in dying cells during lumen formation, and thus, proposed that excessive self-eating may promote cell death in the lumen. However, we now reassess this hypothesis. Because cells in the lumen die due to extracellular matrix (ECM) deprivation (anoikis), we tested if autophagy is regulated by ECM detachment. We discovered that detachment strongly induces autophagy in epithelial cells, even when apoptosis is inhibited by Bcl-2 expression. RNAi-mediated depletion of autophagy-related (ATG) genes inhibits detachment-induced autophagy, resulting in increased apoptosis and reduced clonogenic recovery following anoikis. Similarly, during 3D morphogenesis, ATG-depletion enhances luminal apoptosis and fails to elicit long-term luminal survival and filling, even when combined with apoptotic inhibition. Thus, autophagy promotes epithelial cell survival during anoikis. These results broach the possibility that autophagy contributes to the survival of tumor cells lacking appropriate matrix contact, either during early carcinoma formation or in the later stages of dissemination and metastasis.

Glutaminolysis and autophagy in cancer

“…77,78 Autophagy promotes metastasis by limiting detachment-induced cell death (anoikis) during extracellular matrix detachment of cancer cells. 79 Autophagy also contributes to the survival of dormant disseminated tumor cells for extremely prolonged periods. 80 However, although allelic loss of BECN1 is found in some tumors, 71 the complete deletion of BECN1 has not been observed, which suggests that BECN1 is necessary for tumorigenesis and for the maintenance of the malignant state.…”

Integration of Autophagy and Anoikis Resistance in Solid Tumors

“…Herein, we demonstrate some representative examples of its controversial roles. On one hand, autophagy facilitates the survival and growth of the cancer cells under stressful conditions, such as serum starvation, low attachment, and hypoxia (Levine, 2007;Debnath, 2008;Li et al, 2011;Mohan et al, 2011;Hu et al, 2012a). Indeed, more evidences have arisen to support the hypothesis that autophagy contributes to cell survival circumstantially.…”

“…When normal cells detach from the ECM, they undergo anoikis. Autophagy is also induced following ECM detachment (Debnath, 2008). During this process, anti-apoptotic signals are triggered in transformed cells, allowing the survival of these cells provided they reattach to the ECM in a timely manner (Fung et al, 2008).…”

“…The hypoxia-inducible factor-1a (HIF-1a)/AMP-activated protein kinase (AMPK) pathway mediates the hypoxia-induced autophagy in glioblastomas and prevents apoptotic cell death in vitro (Hu et al, 2012a). The in vitro three-dimensional (3D) cell culture model shows that autophagy can inhibit apoptosis and promote cell survival during anoikis and the lumen formation (Debnath, 2008). In hepatoblastoma (HB), a rare human liver cancer, the Beclin-1 and Atg5-dependent PI3K signaling pathway is supposed to be essential for the survival of HB cells in tolerance to chemotherapy (Chang et al, 2011).…”

“…Hence, anoikis is essential in the maintenance of the physical condition of the whole organism and sustaining tissue homeostasis and development. For example, anoikis promotes the luminal clearance during mammary gland development, which to some extent explains the formation of our inner organ (Debnath, 2008). Moreover, a bulk of evidences has proved that anoikis resistance is intimately involved in the tumorigenesis and metastasis of various cancers, such as lung, colon, and prostate cancers (Horbinski et al, 2010;Broustas et al, 2012;Taddei et al, 2012;Vigil et al, 2012;Zheng et al, 2012).…”