Biology Reference
In-Depth Information
pathways so that a cell can no longer realize that it has lost contact with its basement
membrane. Non-epithelial cells, such as osteoclasts, show a similar dependence on contact
with the extracellular matrix and, because cells each express different types of matrix recep-
tors, only the correct type of matrix will do to promote cell survival.
59
The system is ancient
and in primitive metazoa, such as the cnidarian Hydra, grafts of cells from an unrelated indi-
vidual do not adhere properly to the matrix of the host, and this causes their elimination by
anoikis.
60
Given the great age of the anoikis mechanism, it is not surprising that it has been co-opted
by evolution to play an essential part in several morphogenetic mechanisms in higher
animals. If cells elect to die if they lose contact with their matrix, one way in which they
can be killed off is to arrange for the matrix to be destroyed. This order of events is seen in
the involution of mammary glands, which is the process that returns them to a non-lactating
state when a mother's latest offspring have weaned and no longer require milk. Before preg-
nancy, mammary glands consist of branched milk duct epithelia surrounded my mesen-
chyme and fat deposits. During pregnancy, the epithelia sprout alveoli (Chapter 20) that
make milk but, after weaning, these alveoli disappear by elective cell death in the process
historically called 'involution'. Alveolar epithelial cells depend for their survival on making
contact with components of the alveolar basement membrame, notably laminins that are
bound by
1-integrin-containing receptors.
61
This basement membrane is stable during lacta-
tion, but the transition to involution is heralded by the expression of proteases (for example,
gelatinase A, stromelysin 1) that destroy the proteins in this basement membrane. If the
action of these proteases is inhibited, by implanting into the mammary gland slow-release
pellets of TIMPs (tissue inhibitors of metalloproteases), involution is delayed and the alveolar
cells retain their healthy, differentiated state.
62,63
Conversely, precocious expression of a met-
alloproteinase during lactation resulted in a marked diminution of alveoli and milk produc-
tion.
64
The propensity of cells to undergo anoikis can therefore be used to clear them away
during morphogenetic change. Careful observation of mammary gland involution suggests
that the control of elective cell death is a little more complicated, however. There are two
waves of cell death, the first of which takes place even if the matrix is intact and the second
of which requires matrix destruction.
65
The first wave is associated not with a disappearance
of the matrix, but rather an altered conformation of
b
1-integrin that renders it unable to bind
its matrix.
61
The anoikis mechanism can therefore be exploited from both sides: from the
outside by the removal of matrix and from the inside by the switching off of matrix receptor
activity.
Elimination of epithelial cells that are marooned in mesenchyme after palate fusion
(Chapter 19) may be another example of the use of anoikis by morphogenetic mech-
anisms. Indeed, the hollowing out of embryos and tubes, described earlier in the
chapter, is arguably a related phenomenon, because it is contact with the basement
membrane that spares the lives of cells that surround their dying neighbours in the
cavity. As more is discovered about elective cell death, it may be that anoikis merges
back into the generality of death mechanisms and no longer seems to stand out as a sepa-
rate mechanism.
The overall importance of elective cell death of all kinds to animal morphogenesis can be
illustrated by reducing its extent (for example, by knocking out) or using inhibitors of cas-
pases: the result is widespread and lethal dysmorphogenesis.
66
b
