Anoikis resistance: an essential prerequisite for tumor metastasis

Abstract

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.

Figure 1

Schematic representation of intrinsic and exrtinsic pathways of anoikis. When cells are detached from ECM, normal cells induce anoikis through both intrinsic and exrtinsic pathways. Upon cell detachment, FAS and FasL are upregulated and FLIP is downregulated, leading to activation of Caspase 8, followed by activation of caspase-7 and caspase-3. Loss of cell adhesion also increases and activates proapoptotic Bcl-2 proteins (Bik, Puma, Bad, Noxa, Bmf, Bid, Bim, Bax, and Bak), which inactivate antiapoptotic Bcl-2 proteins (Bcl-2, Bcl-xL, Mcl-1), and thus causing mitochondria membrane permeabilization through Bax/Bak oligomerization. Released cytochrome c from mitochondria activates caspase-9, subsequently caspase-3. Smac/DIABLO is released and inhibits XIAP, an inhibitor of apoptosis, leading to caspase-3 activation. Activaiton of these pathways leads to anoikis. However, increased FLIP expression in cancer cells inhibits extrinsic pathway and oncogene expression such as EGFR and hypoxia downregulate Bmf and Bim, resulting in inhibition of mitochondrial pathway in suspended cells. Accordingly, cancer cells acquire anoikis resistance.

Figure 2

Schematic representation of EMT and anoikis resistance. EMT-inducing factors, such as TGF-β and FGF activate transcriptional factor, Twist, Snail and Zeb1. Activated these transcriptional factors repress E-cadherin (encoded CDH1 gene) expression and induce N-cadherin expression (Cadherin switch). Cadherin switch induces EMT and anoikis resistance, which are associated with tumor metastasis.