Microvascular Permeability and Tumor Metastasis - Bioanalysis Advanced Materials Methods and Devices - page 58

wall in distant organs. Understanding this step may lead to new therapeutic
concepts for tumor metastasis targeting tumor cell arrest and adhesion in the
microcirculation. Microvascular hyperpermeability due to compromised
microvessel wall integrity by inflammatory agents and cytokines is one factor
that increases tumor cell adhesion to the microvessel endothelium.

4.4.1 VEGF Effect on Microvascular Integrity

Vascular endothelial growth factors (VEGFs) are a family of cytokines that act to
increase the delivery of nutrients to tissue by three distinct mechanisms:
(a) endothelial cell growth, migration, and new blood vessel formation (angio-
genesis) [ 21 ], (b) increased blood flow (by vasodilatation) [ 8 ], and (c) increased
vascular permeability to water and solutes [ 7 , 21 , 30 , 31 , 40 , 66 , 86 ]. Combining
in vivo permeability measurement and a mathematical model for the
interendothelial transport, Fu et al. [ 29 ] predicted that the acute effects of
VEGF on microvascular integrity are widened gap opening of the interendothelial
cleft and partial degradation of the ESG. Longer term effects of VEGF include the
formation of gaps between adjacent endothelial cells in venular microvessels [ 56 ],
vesiculovascular organelle pathways [ 25 ], transcellular pores [ 25 , 59 ], and fenes-
tra [ 25 , 66 ]. Fu et al. [ 32 ] also found that the VEGF-induced microvascular
hyperpermeability can be abolished by enhancing intracellular levels of adeno-
sine 3 0 ,5 0 -cyclic monophosphate (cAMP), which strengthens the microvessel
integrity by increasing the number of junction strands in the cleft between
endothelial cells forming the microvessel wall.

4.4.2 VEGF Effect on Tumor Cell Adhesion

Previous studies have found that many cancer cells express VEGF to a high
degree [ 45 ], while the microvascular endothelium has abundant VEGF receptors
including VEGFR2 ( KDR/Flk-1) [ 55 ]. VEGFR2 has been implicated in normal
and pathological vascular endothelial cell biology [ 62 ]. Recently, it has been
shown that ectopic administration of VEGF enhances the adhesion and transmi-
gration of human breast cancer MDA-MB-231 cells across a monolayer of human
brain microvascular endothelial cells under a static condition in vitro [ 45 ].
In addition, VEGF enhances the adhesion of malignant MDA-MB-435 cells and
ErbB2-transformed mouse mammary carcinomas to intact rat mesenteric

microvessels under flow in vivo [ 69 ](Fig. 4.4 ).