Biomedical Engineering Reference
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regulation of MMP expression and that, conversely, highly malignant cells
become less aggressive when MMP activity is reduced. As provided by ovar-
ian cancer transmigration assays, the overexpression of 1-integrins during
the adhesive interactions between neoplastic individuals and the pericellular
matrix results both in the downregulation of the E-cadherin function and in
the activation and co-localization of MMP-2, MMP-9, MMP-14, and MT-1
MMP, which also cleave CD44 molecules, releasing their extracellular domain
[136]. In particular, the activity of the secreted MMPs promotes cancer inva-
sion by cleaving and regulating the normal function of the N-cadherins, which
are the predominant cell{cell adhesion molecules holding the mesothelial cells
together: the breakage of these bonds causes the retraction of the mesothe-
lial layer at the attachment site of malignant cells, opening the way for the
subsequent invasion [305], as shown in Figure 3.3(B-D). In this regard, some
data suggest that the mesothelial cells themselves may produce low levels of
MMPs and induce MMP expression by ovarian cancer cells [405].
Other data have instead shown that ovarian tumor cells secrete the urinary-
type plasminogen (uPA), which participates in the conversion of plasminogen
to plasmin and allows further amplification of submesothelial ECM degrada-
tion, and other serine proteases. However, uPa and serineproteases may play a
less important role than MMPs in facilitating cancer invasion. Upon complete
migration of cancer cells across the mesothelium, the normal function and
signaling of N- and E-cadherins are recovered [345], as the mesothelial cells
rejoin closing the gaps previously created over the migrated malignant cells
[385], as shown in Figures 3.3(E-F). In this respect, we can say that single cell
invasion is conservative [346].
3.1.2 Multicellular Spheroid Invasion
In the ascites of ovarian cancer patients, tumor cells also exfoliate as aggre-
gates or multicellular spheroids, whose most important function is to create an
anchorage-independent in vivo tumor microenvironment, supporting mecha-
nisms of cell survival and growth through homotypic cell{cell adhesion [364].
The initial formation of ovarian spheroids is strongly regulated by 1-integrin
subunits [68], but it is also mediated by compensatory mechanisms, through
other cell{cell interactions, such as gap junctions, tight junctions, and desmo-
somes [425] and the activity of cadherins and different ECM components
(including fibronectin, laminin, and type I and IV collagens), glycosaminogly-
cans, and proteoglycans incorporated into the spheroid from the ascites fluid
[51]. Because of their low proliferative rate, spheroids are resistant to thera-
pies directed against fast-growing tumor cells, to some forms of chemotherapy,
and to apoptosis induced by radiation or by conventional therapeutic drugs
[52, 207]. They have also altered kinetics of drug absorption. This evidence
suggests that spheroids may represent a tenacious and important interme-
diate for secondary tumor growth and an accurate model system of ovarian
metastasis [127, 363].
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