Biomedical Engineering Reference
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fibroblasts of epithelial cancers including lung, colorectal, breast and ovarian
carcinomas, subsets of bone and soft-tissue sarcomas, granulating tissue at
sites of wound-healing, and foetal mesenchymal tissues. 87,88 Additionally,
FAP localizes to the advancing portion ('invadopodia') of cultured malignant
LOX melanoma cells where it contributes to the invasive phenotype. 89
Like the DP4 -/- mice, FAP knockouts display a normal phenotype; thus
a critical role for FAP in foetal development is unlikely. 90 FAP is expressed
by hepatic stellate cells at the tissue remodeling interface in human cirrhosis 91
where its expression is strongly and significantly correlatedwiththeseverity
of liver fibrosis. 92 Further studies in human liver have co-localized FAP
with collagen fibers, fibronectin, and type I collagen. 93 Heterologous over-
expression of FAP results in reduced adhesion and migration of human
embryonic kidney (HEK)-293T cells. 93 In contrast, the same study found that
over-expression of FAP in the human hepatic stellate line, LX-2, resulted in
increased adhesion and migration of cells to extracellular matrix proteins and
invasion across transwells, independent of transforming/tumour growth
factor beta (TGF-b). 93 In both HEK-293T and LX-2 cell lines, FAP over
expression resulted in enhanced staurosporine streptomyces-stimulated
apoptosis. 93 It may be possible that, because of its roles in tissue remodeling
and wound healing, FAP mRNA is kept at low levels in most cell/tissue types
to initiate a quick response in the event of external damage. FAP expression
can be upregulated by TGF-b,12-O-tetradecanoyl phorbol-13-acetate (TPA)
and retinoids (chemical compounds related to vitamin A). 94 TGF-b is a
ubiquitously expressed cytokine shown to play central roles in numerous
processes including FAP relevant wound healing, tissue repair, fibrosis, and
cancer (reviewed in several previous studies 95-98 ). FAP is also expressed at the
remodeling interface of idiopathic pulmonary fibrosis (IPF), 99 a progressive
and debilitating disease of the lung. TGF-b is likely to play a key role in the
mediation of IPF. 100 Soluble FAP has been purified from bovine serum 29 and
has been identified as the antiplasmin-cleaving enzyme (APCE) in humans. 101
FAP is responsible for cleavage and increased activity of the human plasmin
inhibitor, a 2 -antiplasmin (a 2 AP), 28 thus further supporting the pro-fibrotic
role of FAP and its early involvement in wound healing.
Co-expression of FAP and DP4 results in heteromeric complex formation on
the cell surface of COS-1 cells. 102 DP4-FAP expression is found in reactive
fibroblasts of healing wounds 102 and has been localized to invadopodia of
migratory cells. 103 In vivo DP4 and FAP colocalize on capillary endothelial
cells, but not large blood vessels in invasive breast ductal carcinoma. 104 DP4-
FAP complex formation is important in the development of the tissue-invasive
phenotype in migratory cells during wound healing 103 and plays an important
role in the migration and invasion of migratory fibroblasts and human endo-
thelial cells in collagenous matrices. 103,104 This is likely to involve localized
DP4-FAP gelatin degradation. Blocking of the gelatin-binding domain of DP4
in the DP4-FAP complex blocks local gelatin degradation by endothelial and
migratory fibroblasts and alters migration and invasion of cells on collagenous
matrices. 104
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