Live free or die: tales of homeless (cells) in cancer

Abstract

Anoikis, programed cell death that occurs on cell detachment from the extracellular matrix, thus disrupting integrin-ligand interactions, is a critical mechanism in preventing ectopic cell growth or attachment to an inappropriate matrix. Anoikis prevents shed epithelial cells from colonizing elsewhere and is thus essential for maintaining tissue organization. Lack of integrin ligation leads to decreased focal adhesion kinase and integrin-linked kinase activity, which impairs downstream survival signaling. Consequently, targeting tumor cell survival by triggering anoikis provides a unique molecular basis for novel therapeutic targeting of tumors before initiation of metastasis. The two major cell death pathways involved in anoikis signaling are apoptosis and autophagy; growing evidence suggests an extensive cross-talk between the two killing modes as well as context-dependent cooperation and antagonism. This review discusses the functional integration between the two modes of cell death converging at anoikis, including key molecules of interaction such as Beclin 1, reactive oxygen species, extracellular signal-related kinase, and death-associated protein kinase. The involvement of other apoptotic effectors such as Bcl-2, p53, and FLICE inhibitory protein in cancer cell anoikis is also discussed. Dissecting the mechanistic players in the cellular response may be of high clinical significance in identifying effective approaches in reversing anoikis resistance in primary tumor cells and, consequently, impairing metastasis.

Figure 1

Cross-talks of death: encounters between autophagy and apoptosis converge in anoikis. Key points of functional exchange and signaling interactions engage integrin-stimulated ROS, DAPk, Beclin 1, and ERK. The activity of BCL-2 family members is multifaceted. The family consists of the antiapoptotic group, including the major apoptosis suppressor Bcl-2; the proapoptotic “multi-BH domain” group, including Bax and Bak; and the proapoptotic “BH3-only” group, including Bid. It is the ratio of pro- and antiapoptotic proteins that controls the cellular vulnerability to apoptosis. Bcl-2 helps maintain both mitochondrial membrane homeostasis and calcium homeostasis within the cell. Bax and Bak can respond to an intrinsic death stimulus by translocating (Bax), oligomerizing and inserting into the outer mitochondrial membrane to promote permeabilization. Proteolytic Bid cleavage mediated by caspase-8 leads to Bid myristoylation, mitochondrial localization, and MOMP induction, an event that suggests a cross-talk event between the two major apoptotic pathways. E-cadherin regulates the desmosomal junctions and its loss confers resistance to anoikis. All players act as transducers between cell-cell and cell-extracellular matrix signals to promote autophagy and/or apoptosis, either resulting in the death of the detached cell or enhanced survival toward metastatic spread. INT, integrins; cyt c, cytochrome c; Δψmt, mitochondrial membrane potential.