ReviewAnoikis mechanisms
Introduction
Normal cell and tissue homeostasis reflects a dynamic balance of cell proliferation, differentiation and apoptosis. Anoikis—the subset of apoptosis triggered by inadequate or inappropriate cell–matrix contacts — maintains the correct cell number of high-turnover epithelial tissues. The clearest evidence for this is that the breakdown of anoikis contributes to neoplasia. Accordingly, this process is discussed first.Fig. 1[73]
Section snippets
Recent evidence for a role of anoikis resistance in malignancy
Anoikis was first documented in both epithelial cells— the precursors of most human cancers—and endothelial cells. In these early reports [1], [2], the expression of certain oncogenes was shown to render normal epithelial cells resistant to anoikis. More recent reports confirm that the breakdown of anoikis contributes prominently to the malignancy of mammary and colon cancers [3], [4], [5]; a similar role has recently been reported for lung carcinomas (see Now in press).
The breakdown of anoikis
Role of protein kinase signaling pathways in anoikis
Numerous kinase/phosphatase signaling molecules have been implicated in anoikis as central regulators. Because ras activation prevents anoikis [1] and integrins can stimulate various aspects of the ras pathway, anoikis research has focused on the two major ras effectors, the kinases PI3K (phosphoinositide-3 kinase) and raf. Rather than cataloguing the signaling molecules that we may infer to control anoikis, the next section focuses on some recent findings regarding selected signaling pathways;
Role of the cytoskeleton
The readily apparent differences between the cytoskeletal structures of attached versus suspended cells suggest that survival signaling in anoikis is likely to be extensively regulated by cytoskeleton. Such regulation may be affected by the multiple cytoskeletal changes apparent in transformed cells [49]. Indeed, substantial evidence now exists that both signaling molecules and apoptosis regulators are associated with the cytoskeleton, and as such may together regulate anoikis by serving as
Role of death receptors in anoikis
One of the major outstanding questions in anoikis research is how the caspase cascade is initially activated by simple detachment of cells from the matrix. One hypothesis is that death receptors somehow become activated, either through their propensity for self-association—which may suffice for signaling—or by an interaction with endogenous death ligands.
Recent results indicate that the death receptor adaptor molecule FADD may be involved in anoikis, as a dominant-negative truncated FADD
Conclusions
It is evident that much work remains to be done to establish mechanistic linkages between cell adhesion and apoptosis. Two new frontiers for research have recently emerged: the involvement of the cytoskeleton and the role of the gene expression program.
The architectural state of the cytoskeleton is expected to affect the interactions of signaling molecules in three-dimensional space. Currently one of the challenges of anoikis research is to connect cytoskeletal organization (as opposed to
Update
Two additional reports relevant to this review were recently published [71], [72].
The first relates to the phenomenon that fibronectin adhesion of CHO-based stable transfectants that express α5 β1 integrin protects against apoptosis under serum-starved conditions but adhesion to vitronectin does not. This protection correlates with bcl-2 expression levels, and reference [71] reports that the bcl-2 promoter is regulated by signaling molecules such as FAK, Shc and Akt that may respond to specific
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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