Biomedical Engineering Reference
In-Depth Information
Human DP4 is ubiquitously expressed in a wide variety of tissues and cell
types, exerting its functions on a broad range of physiological processes
within the human body. DP4 is expressed at high levels on the surface of
several endothelial, epithelial, and fibroblast cells of the lung, kidney, liver,
intestine, bile duct, and other organs, thus affecting the gastrointestinal/
digestive, cardiovascular, endocrine, neurological, and immunological sys-
tems. 60,61 In kidney, DP4 is one of the major microvillus membrane/brush-
border membrane proteins. 62 Relatively high levels of soluble DP4 activity are
observed in human bodily fluids, 63-65 and thus the activity of soluble, circu-
lating DP4 is likely to also contribute to effects observed in many of these
systems. Variations in the level of serum DP4 activity have been associated
with numerous diseases, and the effectiveness of measuring soluble DP4
activity levels as a biomarker for diagnosis, monitoring, and prognosis of
diseases such as cancer, arthritis, and psychiatric disorders has been investi-
gated. 66-72 In the immune system, expression of DP4, known as the surface
antigen CD26, is detectable at low levels on the surface of some resting T cells,
B cells, and natural killer (NK) cells. 73-75 DP4 functions as a co-stimulatory
molecule of T-cell activation, displaying increased expression on the cell
surface of activated T-cells. 73 On the surface of B cells, DP4 expression is
upregulated following the immunogenic stimulation of B cells with pokeweed
mitogen 76 or the Staphlococcus aureus-derived immunogen streptokinase. 77
Despite the widespread involvement of DP4 in animal biology, the absence of
DP4 expression does not result in any known adverse defects, as demon-
strated by the apparent healthy phenotype of knockout DP4 mice (DP4 -/- ) 78
and their favorable protection against diet-induced obesity and associated
insulin resistance. 79 Recently, studies investigating the long-term chronic loss
of DP4 expression in genetically induced DP4 deficient rats have identified
some age-dependent alterations in immune system composition and stress-
regulatory responses. 80,81 Of interest to human pathological conditions,
particularly cancer, is the apparent loss of DP4 expression during disease
progression. Loss or alteration of DP4 surface expression has been observed
in several malignant cells and carcinomas such as lung, breast and ovarian,
prostate, 82,83 and colon adenocarcinoma 84 and during the progression of
melanocytes to melanoma. 85,86 It should be made clear, however, that loss of
DP4 expression is not a hallmark of all cancers with many studies examining
the expression and roles of DP4 in cancer producing conflicting results. In
fact, DP4 upregulation has been observed in differing cancer studies to con-
tribute to the metastatic cancer phenotype, thus acting as a tumor promoter
contributing to disease progression.
In contrast to DP4, FAP displays a more restricted and specific pattern of
expression in adult humans. Detection of translated human FAP in normal
adult tissue with the F19 monoclonal antibody is limited to the occasional
fibroblasts and a subset of pancreatic islet cells. 87 Results of a master RNA
blot provide evidence for there being a more ubiquitous pattern of FAP
expression at the transcript level
in tissues where protein has not been
detected. 52
FAP protein is most widely expressed in reactive stromal
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