Vascular Endothelium in Inflammation and Metastasis 
importantly to the control of inflammatory pro- 
cesses. Acute inflammation is of relatively short 
duration, lasting as little as a few minutes or as 
long as 1 - 2 days. It is characterized by the exuda- 
tion of plasma proteins and the emigration of leu- 
kocytes, especially neutrophils. Chronic inflam- 
mation is of longer duration and is associated 
with the extravasation of blood lymphocytes and 
macrophages and with the morphological changes 
in blood vessels and connective tissues. 
In most cases the pattern of E-selectin expres- 
sion correlates well with acute inflammation. 
This observation is consistent with the demonstra- 
tion that E-selectin supports the adhesion of es- 
sentially all neutrophils, but only a small portion 
of lymphocytes. In contrast, INCAM-1 10 (known 
also as VCAM-1) supports the adhesion of lym- 
phocytes but not neutrophils, and its pattern of 
expression is consistent with its primary role in 
chronic inflammatory processes. 
The inflammatory process is essential for host 
defense. In certain settings, however, it can also 
contribute to debilitating and life-threatening 
diseases. Examples of human diseases with signifi- 
cant inflammatory/immunological components 
are adult respiratory distress syndrome (ARDS), 
myocardial reperfusion injury, rheumatoid ar- 
thritis, and various autoimmune diseases. Un- 
derstanding the mechanisms of endothelial- 
leukocyte adhesion may allow us to enhance our 
defense mechanisms, or dampen their responses 
when appropriate. 
Vascular Selectins and Their 
Carbohydrate Ligands 
Each of the three selectins is a cell-surface gly- 
coprotein with a mosaic structure. The portion of 
the molecule that is external to the cell, and 
hence reaches out into the bloodstream, contains 
a lectin domain. Lectins are protein molecules 
that bind to carbohydrates (sugars) . Our labora- 
tory is utilizing the recombinant E- and P-selectin 
proteins and soluble synthetic carbohydrates to 
determine the structures involved in recognition. 
Early studies had suggested that E-selectin me- 
diates the adhesion of blood leukocytes through 
the binding of a carbohydrate known as sialyl- 
Lewis X. This structure contains a terminal 
sialic acid as well as a fucose group bound to 
a carbohydrate backbone of galactose and A'^ 
acetylglucosamine. Surprisingly, we demon- 
strated that a soluble form of sialyl-Lewis X was 
only a modest inhibitor of E-selectin-dependent 
adhesion, whereas a related carbohydrate called 
sialyl-Lewis A, difi'ering only in the linkage of the 
backbone sugars, was much more effective. Sialyl- 
Lewis A is not found on blood neutrophils but is 
expressed by a variety of cancers, including those 
of the colon. The relative blocking activities of 
sialyl-Lewis X and sialyl-Lewis A were reversed 
for P-selectin. 
In addition, a third carbohydrate compound 
designated CD65, which is found on leukocytes 
and some cancer cells, was shown to be an efl'ec- 
tive blocker of adhesion to both E- and P-selectin. 
Subsequent studies using modified carbohydrates 
have demonstrated that the presence and precise 
arrangement of sialic acid and fucose are impor- 
tant in the recognition by the two selectins. Fur- 
thermore, minor modifications in the carbohy- 
drate structures can result in greatly increased 
activity in blocking leukocyte adhesion. 
A Possible Role in Cancer Metastasis 
If cancers grew and invaded tissues locally but 
failed to metastasize, most of them could be 
cured by surgery. Indeed, the lethal effects of a 
cancer are generally ascribed to its metastatic 
abilities. Hematogenous metastasis involves re- 
lease of cells from a primary tumor into blood 
vessels and transport to new tissues. Substantial 
evidence indicates, however, that the blood is 
hostile to cancer cells and generally destroys 
them. Thus most cancer cells must exit the 
bloodstream in order to survive. Our laboratory 
has focused on the mechanisms by which tumor 
cells bind the vessel wall and extravasate. We 
now appreciate that many tumor cells can inter- 
act with the vascular endothelium through the 
same molecules blood leukocytes use. 
As noted above, colon cancers can express car- 
bohydrate ligands for E-selectin. In a parallel line 
of investigation, we have demonstrated that hu- 
man melanomas can express the integrin a4l3l, 
which is a receptor for the endothelial cell- 
surface molecule INCAM-1 10 or VCAM-1. These 
observations suggest the possibility of novel ther- 
apeutic approaches to block the metastatic 
spread of cancer. 
In summary, vascular endothelium can exist in 
different functional states. These states are deter- 
mined by stimuli such as cytokines and bacterial 
products. Activated endothelial cells express ad- 
hesion molecules for circulating leukocytes and 
can thereby regulate inflammatory processes. In 
addition, it appears that cancer cells can utilize 
these same adhesion molecules during the pro- 
cess of hematogenous metastasis. 
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