Induction of Autophagy during Extracellular Matrix Detachment Promotes Cell Survival

Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Molecular biology of the cell (Impact Factor: 4.47). 04/2008; 19(3):797-806. DOI: 10.1091/mbc.E07-10-1092
Source: PubMed


Autophagy has been proposed to promote cell death during lumen formation in three-dimensional mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells after detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring antiapoptotic lesions.

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    • "lack or low levels of nutrient supply and oxygen in spite of high metabolic requirements) (Levine et al., 2007). Moreover, autophagy seems to confer resistance to anoikis, protecting cells from death following detachment from the basal lamina (Fung et al., 2008). This facilitates cancer cell escape from primary tumors, leading to cancer invasion and spread. "
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    • "Both under basal and stressful conditions, enhanced levels of autophagy were detected only in ECM-detached conditions (2D cultures) [6]. Similarly, Fung et al. demonstrated autophagy induction in response to a lack of ECM contact (cells present in the central acinar region) during the mammary lumen development [84] . Numerous matrix constituents (decorin, collagen , laminin, endostatin and endorepellin) have been described as autophagy modulators. "
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    • "When cells are detached from the ECM, cell signalization is interrupted, and they may undergo anoikis. Autophagy is largely used by cancer cells in order to avoid anoikis and induce the later stages of cancer progression , such as dissemination and metastasis [48,49] . Subpopulation of cells within tumors, termed cancer stem cells, is responsible for tumor recurrence and metastasis. "
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