Biomedical Engineering Reference
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coherent, membrane-encapsulated apoptotic bodies [
4
,
25
,
44
,
46
], which are
finally phagocytosed (ingested) and degraded by macrophages or other nearby
cells [
25
,
44
]. See Fig.
2
(top: e). For more information on apoptosis, the reader is
encouraged to consult several excellent reviews (e.g., [
25
,
44
,
46
,
65
,
87
]).
2.1.1 Estimates of Apoptosis Time Scales
In [
55
-
57
], Macklin et al. analyzed the experimental biology and clinical literature
to estimate the main apoptosis time scales. The overall duration of apoptosis
was estimated at 8-9 h, with an approximately 2 h lag until detectable cleaved
Caspase-3 activity, and an additional hour of lag prior to detection by TUNEL
assay. Mumenthaler et al. are now directly measuring these and other apoptosis
time scales with in vitro experiments on MCF-7 and related breast cancer cell lines
[
68
]. In preliminary results, we observed cell water loss to be very fast: most water
is lost within the first hour of apoptosis. We also observed that the cytoplasm
blebbs and loses much of its volume within 3 h, leaving a degrading nucleus for
the remainder of apoptosis. These preliminary observations are consistent with
other experiments (e.g., [
30
,
88
]), which estimated apoptosis to last 8-9 h [
30
],
and measured rapid 60 % volume losses early in apoptosis [
88
].
2.2 Basic Biology of Necrosis and Calcification
In contrast to apoptosis, necrosis is a relatively energy-independent process,
spanning a variety of time and spatial scales [
46
,
66
]. In the context of cancer
biology, necrosis is most frequently the result of cellular energy depletion, rather
than a ''planned'' event [
6
]. Thus, while apoptotic cells generally appear sporad-
ically as isolated, shrunken cells, necrotic tumor cells are found in large contig-
uous regions (i.e., necrotic cores) where oxygen and glucose are too low to sustain
cell survival [
44
,
87
]. Necrosis also differs from apoptosis in that it triggers an
inflammatory response, due to the dysregulated release of intracellular proteins
into the microenvironment [
6
,
46
]. Indeed, inflammatory responses can readily be
seen in pathology images near necrotic tumors; see Fig.
1
(right) for one such
example.
In the early stages of necrosis (more properly called oncosis [
46
,
65
]), energy
depletion causes the cell's ion pumps to shut down, resulting in rapid swelling by
osmosis. This swelling has traditionally been a key feature differentiating necrotic/
on-co-tic cell death from apoptotic cell death in pathology and in vitro biology
[
44
,
46
,
65
]. The cell swells to several times its original volume, lyses (splits
open), and slowly leaks fluids and other protein contents into the surrounding
microenvironment [
46
]. See Fig.
3
(top: a-c and bottom: left). Disintegrating
lysosomes can release enzymes that help to further degrade the cell [
6
]. As in
apoptosis, the nucleus displays some (irregular) chromatin condensation and
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