Biology Reference
In-Depth Information
signals that may be permissive for the migration of one cell type may not be
permissive, or in fact may be inhibitory, for the migration of other cell types.
For example, leukocytes can navigate through diverse extracellular environ-
ments as a normal part of immune surveillance. This basic principle raises
interesting questions about what makes a leukocyte migratory in what may
otherwise be non-permissive tissues and the changes that occur in metastatic
cancer that trigger the invasive properties of cells.
Central to this premise is the existence of migration-inhibiting cues. An
important migration-inhibiting external signal is mediated by the extracellular
matrix mileu. For example, certain extracellular matrix components at high
density, such as fibronectin, may be inhibitory to cell migration. In fact, many
cell types exhibit a biphasic relationship between adhesion and migration rate,
with optimum speed occurring at an intermediate cell-substratum adhesive-
ness (Huttenlocher et al., 1996). Migration is inhibited at lower than optimal
cell-substratum adhesiveness presumably because cells cannot form stable
adhesions; conversely, at higher than optimal conditions, previous studies
have suggested that migration may be inhibited because cells cannot
effectively release adhesions at the cell's rear (Huttenlocher et al., 1995).
However, recent studies suggest that ligand-density dependent regulation of
intracellular signalling and cell polarization/protrusion may also be an
important mechanism by which high density of ligand inhibits cell migration
(Cox et al., 2001). More specifically, these studies demonstrated that high
fibronectin density down-regulates signalling pathways via Rac and Cdc42,
critical for cell protrusion and polarization, thereby inhibiting cell migration.
A related, but less understood mechanism, may also contribute a migration-
inhibiting cue. This mechanism involves contact-mediated inhibition of cell
movement, with suppression of motility upon contact between specific cell
types. Contact-mediated inhibition of cell migration was initially detailed by
Abercrombie et al. to describe the inhibition of migration and motile activity
that occurs after cell-cell contact in migrating fibroblasts (Trinkaus, 1984). In
fibroblasts, after contact between ruing membrane surfaces of adjacent cells
the regions become quiescent and the cells appear to attach to each other,
while other regions of the cells continue to rue. Subsequently, the cells will
detach and migrate in the opposite direction. Contact inhibition is more
extreme in epithelial cells, which tend to remain attached via cadherin-
mediated cell-cell adhesion following contact. The contact inhibition and
more stable contacts that form between epithelial cells provide an important
mechanism to limit the invasive characteristics of carcinomas (Frixen et al.,
1991). Although cadherin-mediated cell-cell adhesion inhibits the invasiveness
of tumours, its role in contact-mediated inhibition of motility has not been
clearly defined, although it is possible that cross-talk between integrins
and cadherins modulates contact-mediated inhibition of motile activity
(Huttenlocher et al., 1998).
