The
serine protease fibroblast activation
protein (FAP) is selectively expressed on tumour-associated fibroblasts in most human epithelial tumours, as well as on some mesenchymal tumours such as
sarcoma. High FAP expression is most often associated with poor outcome and increased
metastasis. Here, we compare the in vitro metastatic potential of HT1080
fibrosarcoma cells with and without FAP expression in order to elucidate the mechanism by which FAP may influence
metastasis. In the presence of FAP, cells were more adhesive to
extracellular matrix proteins and migrated and invaded through
Matrigel to a greater degree. The anti-FAP antibody ESC11, which caused internalization of FAP, decreased adhesion and migration, but only when cells expressed FAP. It was also found that blocking activity of
integrins β1 and αvβ3 reduced both cell adhesion and migration and this effect was much more marked in FAP-expressing HT1080 cells than mock-transfected HT1080 cells. The expression or activation of intracellular
proteins that form part of the downstream signaling of
integrins, including
integrin-linked kinase, Rac1 and
focal adhesion kinase, was also upregulated when FAP was expressed, suggesting that FAP not only upregulates metastatic-like cell behaviours through interaction with
integrins, but also influences the intracellular signaling of
integrins. This was confirmed using both
PI3 kinase and
Src kinase inhibitors, which decreased adhesion and migration in FAP-expressing cells, but did not affect mock-transfected HT1080 cells. FAP is therefore a useful target for anti-
cancer therapy, as not only is its expression tumour-selective, but its downregulation has the potential to reduce incidence of
metastasis.