Microvascular Permeability and Tumor Metastasis - Bioanalysis Advanced Materials Methods and Devices - page 62

conditions. Therefore, the geometry of the microvasculature and the local hydrody-
namic factors, along with the cell adhesion molecules at the tumor cell and endothe-
lial cell should play a crucial role in tumor cell adhesion and extravasation. Tumor
cells are exposed to flow while (a) circulating from the primary tumor, (b) arresting
on the downstream vascular endothelium, and (c) transmigrating into the secondary
target organ. Investigations of the role of shear flow in tumor cell adhesion and
extravasation will contribute to the understanding of the complex process of tumor
metastasis. Tumor cell extravasation would normally occur in the microvasculature
where shear forces are relatively low (like in post-capillary venules) although of
sufficient magnitudes to activate cell surface receptors and alter vascular cell func-
tion. During tumor cell extravasation there are significant changes in the structure and
function of both tumor and endothelial cells. For example a significant rearrangement
of the cell cytoskeleton is required in both the tumor cells during migration [ 44 ]and
in the endothelial cells as the barrier function is altered [ 81 ]. The extravasation of
tumor cells also induces endothelial cell remodeling [ 43 ].
In an in vitro flow chamber study, Slattery et al. [ 71 ] found that the shear
rate, rather than the shear stress, plays a more significant role in PMN (polymor-
phonuclear neutrophils)-facilitated melanoma adhesion and extravasation.

2
integrins/ICAM-1 adhesion mechanisms were examined and the results indicate
LFA (lymphocyte function-associated)-1 and Mac-1 (CD11b/CD18) cooperate to
mediate the PMN-EC (endothelial cell)-melanoma interactions under shear
conditions. In addition, endogenously produced IL-8 contributes to
PMN-facilitated melanoma arrest on the EC through the CXC chemokine receptors
1 and 2 (CXCR1 and CXCR2) on PMN [ 49 , 71 ].

b

4.5 Summary and Future Study

Although transport across the endothelium is a classic problem that has been
investigated for more than several decades, the fundamental questions related to
the structure-transport function of the microvessel wall and the interaction between
the circulating cells and the cells forming the wall still remain unclear. With the
help of mathematical models for more accurate interpretations and predictions, new
techniques involving transgenic animals with fluorescent proteins expressed endo-
thelial cells and circulating blood and tumor cells, new fluorescent dyes for labeling
the structural components of transvascular pathways, intravital and electron micros-
copy, and new developments in molecular biology and biochemistry will lead to
more fascinating discoveries in this field.
One problem is the development of models for dynamic water and solute
transport through multi-transvascular pathways including intercellular,
transcellular, fenestral, and vesicle routes. They are important for predicting the
malfunction in the transvascular process in disease. Another problem is to create
transvascular models for cells such as leukocytes and cancer cells. The transport of
cells is crucial in many physiological and pathological processes including inflam-
matory response and tumor metastasis.