Biomedical Engineering Reference
In-Depth Information
because of its apparent upregulation in multiple metastatic tumor types [
35
]. The
b
4
integrin is unique among integrins, because the cytoplasmic portion of the
4
subunit is 1,017 amino-acid-long and possesses distinctive adhesive and signaling
functions [
35
]. Upon binding of the ectodomain of
b
b
4 to the basement membrane
b
protein laminin-5, the cytoplasmic portion of
4 interacts with the keratin cytoskel-
eton to promote the assembly of hemidesmosomal adhesions [
51
]. In addition,
b
4 activates intracellular signaling autonomously as well as by associating with
multiple receptor tyrosine kinases (RTKs), including the EGFR, ErbB2, Met, and
Ron [
38
,
60
]. Deletion of the
b
4 signaling domain delayed mammary tumor onset
and inhibited primary tumor growth. The tumors arising in mutant mice were
significantly more differentiated histologically as compared to control tumors.
In addition, primary tumor cells expressing signaling-defective
4 displayed a
reduced proliferative rate and invasive ability and underwent apoptosis when
deprived of matrix adhesion. Finally, upon injection in the tail vein of nude mice,
the mammary tumor cells expressing mutant
b
b
4 exhibited reduced ability to
metastasize to the lung [
39
].
Most recently, Fan et al. [
24
] have examined the adhesion of ErbB2-transformed
mammary tumor cells to mouse brain microvascular endothelial monolayer.
They found that integrin
4 signaling does not exert a direct effect on adhesion to
the endothelium or the underlying basement membrane. Rather, it enhances
ErbB2-dependent expression of VEGF by tumor cells. VEGF in turn partially
disrupts the tight and adherent junctions that maintain the adhesion between
endothelial cells, enabling tumor cells to intercalate between endothelial cells and
extend projections reaching the underlying exposed basement membrane, and
enabling adhesion to occur between cell adhesion molecules (e.g., integrins) and
ECM proteins (e.g., laminins).
b
4.4.4 Reducing Tumor Cell Adhesion by Enhancing
Microvessel Wall Integrity
In addition to blocking the cell adhesion molecules at the surface of tumor and
endothelial cells or in the ECM, e.g., integrins, ICAM-1, P-selectins, junctional
adhesion molecules, and laminins, Shen et al. [
69
] measured cancer cell adhesion
after pretreatment of cells with the antibody blocking VEGF, and pretreatment of
the microvessel with VEGF receptor (KDR/Flk-1) inhibitor, SU1498. They found
that anti-VEGF and SU1498 almost completely abolished the adhesion of malig-
nant MDA-MB-435s to vascular endothelium in vivo. In an in vitro experiment,
Fan et al. [
24
] showed that although VEGF receptor (KDR/Flk-1) inhibitor SU1498
did not decrease the basal permeability of a microvascular endothelial monolayer,
nor tumor cell adhesion under the normal permeability conditions. It, however,
abolished microvascular hyperpermeability induced by VEGF as well as increasing
tumor cell adhesion (Fig.
4.5
).
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