Metastasis is a multistep process including dissociation of cancer cells from primary sites, survival in the vascular system, and proliferation in distant target organs. As a barrier to metastasis, cells normally undergo an apoptotic process known as “anoikis,” a form of cell death due to loss of contact with the extracellular matrix or neighboring cells. Cancer cells acquire anoikis resistance to survive after detachment from the primary sites and travel through the circulatory and lymphatic systems to disseminate throughout the body. Because recent technological advances enable us to detect rare circulating tumor cells, which are anoikis resistant, currently, anoikis resistance becomes a hot topic in cancer research. Detailed molecular and functional analyses of anoikis resistant cells may provide insight into the biology of cancer metastasis and identify novel therapeutic targets for prevention of cancer dissemination. This paper comprehensively describes recent investigations of the molecular and cellular mechanisms underlying anoikis and anoikis resistance in relation to intrinsic and extrinsic death signaling, epithelial-mesenchymal transition, growth factor receptors, energy metabolism, reactive oxygen species, membrane microdomains, and lipid rafts. 1. Introduction Development, differentiation, and homeostasis are controlled by cell-cell interactions, cell-extracellular matrix (ECM) interactions, and soluble cues (hormones, cytokines, and growth factors) [1, 2]. Cell adhesion to ECM occurs through interactions between specific integrin receptors and ECM counterparts. These interactions cause the transduction of many different signals that regulate cellular functions, such as gene expression, differentiation, proliferation, and motility. Importantly, an appropriate adhesion to ECM components determines whether a cell is in the correct location and thus regulates cell survival and cell death. In 1994, Frisch and Francis noticed that loss of matrix attachment of epithelial cells resulted in apoptosis [3]. They referred to this form of programmed cell death that occurs upon detachment from the appropriate ECM as anoikis [4–6]. Because anoikis prevents detached epithelial cells from colonizing elsewhere, thereby inhibiting dysplastic cell growth or attachment to an inappropriate matrix, anoikis is a physiologically relevant process for tissue homeostasis and development. Dysregulation of anoikis, such as anoikis resistance, is a critical mechanism in tumor metastasis. Epithelial cancers initially arise as an organ-confined lesion, but eventually
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