Biomedical Engineering Reference
In-Depth Information
layer generally disaggregates and retracts, and that isolated mesothelial cells
beneath the cancer cells die, the target volume A
surfac
M
of a virtual mesothe-
lial cells surrounded by the malignant mass (30 px of common surface) is set to
decrease 1 px each MCS until the limit value of 80 px, for which they undergo
apoptosis.
Figure 3.8 shows a typical simulation of a time-sequence spheroid invasion
of a mesothelial layer: w.r.t. a single individual, the tumor mass takes a longer
time to attach to ECM components (see Figure 3.8(A-B)) and to invade the
layer (see Figure 3.8(C-G)). At the end of the simulated process, multiple
invading foci merge and are able to overtake the well, leaving little of the
monolayer intact by inducing apoptosis of the isolated mesothelial cells. It is
clear that the malignant cells disseminate not only in the same plane, but
also above and below the virtual mesothelium, and degrade a large part of
the ECM components, as shown in Figure 3.8(H). Also in the case of the
multicellular aggregate, an increase in MMP release causes an acceleration in
the overall metastatic program (top panels of Figure 3.9), in agreement with
experimental observations correlating the level of proteolytic enzymes secreted
by tumor spheroids with a poorer prognosis of the disease [122].
Low J
C;C
values (J
C;C
J
C;M
;J
C;E
) model the preference of the spheroid
cells to maintain their strong homotypic connections, rather than disseminate
and establish heterotypic interactions with mesothelial cells or matrix compo-
nents: in this case, the multicellular aggregate shows the tendency to form only
a single focus of invasion. In contrast, for high J
C;C
(J
C;C
J
C;M
;J
C;E
), the
cancer cells quickly detach from the core of the spheroid and disseminate over
a larger area of the mesothelial layer, invading in different sites (middle panels
of Figure 3.9). A similar invasive phenotype can be also obtained by forcing
an overexpression of 1-integrins in the tumor mass by strongly decreasing
J
C;E
(J
C;E
J
C;M
;J
C;C
); bottom panels of Figure 3.9.
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