by Steven M. Frisch, The Burnham Institute, La Jolla, CA, USA, sfrisch at burnham-inst.org
Anoikis is the apoptosis of cells that have lost contact with extracellular matrix, or that interact with matrix through an inappropriate integrin-matrix combination.
- Documented to occur in epithelial, endothelial, muscle cells and oligodendrocytes; also occurs in fibroblasts subjected to growth factor deprivation, possibly by different mechanisms;
- occurs through established apoptotic signaling pathways, which depend upon cell type. These include caspases of both the initiator (caspase-8) and effector (caspase-3,7) types as well as protein kinases such as MEKK- 1/JNK; protection against anoikis is afforded by the activation of certain other kinases such as FAK and Akt. Bcl-2/Bcl-xL involvement depends upon cell type;
- in certain epithelial cell lines, cells must achieve complete cell-cell contact while attached to matrix, to become sensitive to anoikis;
- transformation by oncogenes or loss of tumor suppressor genes can render tumor cells resistant to anoikis, promoting anchorage independent growth/metastasis.
Cellular and molecular aspects
- Cells undergoing anoikis-typical apoptotic characteristics: nucleosomal DNA ladder formation, cell shrinkage, caspase activation/cleavage of caspase substrates, cytochrome c release from mitochondria;
- anoikis is defined operationally, so whether a cell dies from cell-matrix dissociation or from another stimulus can only be determined experimentally, not retrospectively in vivo.
- Anoikis is thought to be relevant to normal tissue homeostasis of rapid turnover epithelial tissues such as in the digestive tract. It is also important for embryonic development (gastrulation) and mammary gland involution;
- sensitivity to anoikis is frequently lost in tumor cells, which probably contributes to their ability to grow independently of anchorage, and metastasize. It is also involved in muscle degeneration in muscular dystrophy;
- this sensitivity can be lost by activated oncogenes such as ras, alterations in intracellular apoptosis components, overexpression of growth factors such as EGF, HGF or IGF-related molecules, or breakdown of cadherincatenin complexes.
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