Fibroblast Activation Protein: A Cell Surface Dipeptidyl Peptidase and Gelatinase Expressed by Stellate Cells At the Tissue Remodelling Interface in Human Cirrhosis

Abstract

Fibroblast activation protein (FAP) is a plasma membranebound atypical serine protease of the prolyl oligopeptidase gene family and is expressed at sites of tissue remodelling. 1,2 FAP was initially described as the cell surface antigen recognized by monoclonal antibody (mAb) F19 on subsets of human astrocytoma and sarcoma cell lines in vitro. 3,4 Subsequent immunohistochemical studies demonstrated that FAP, while not expressed in most normal adult human tissues, is strongly expressed by the reactive tumor stromal fibroblasts surrounding the newly formed blood vessels of epithelial cancers. 5 In addition, FAP-expressing reactive fibroblasts are found in the granulation tissue of healing wounds and in certain fetal mesenchymal tissues. 2,5 Based on the highly selective expression of FAP, in vivo targeting of the tumor stromal compartment has been achieved with radiolabeled anti-FAP mAb F19 in patients with colorectal cancer. 6 Molecular cloning and sequence analysis of a human FAP cDNA and biochemical studies with FAP-specific mAbs have identified the gene product as an N-glycosylated, type II integral membrane protein with a molecular weight of about 95,000, comprising a large carboxy-terminal extracellular domain, a hydrophobic transmembrane segment, and a short cytoplasmic tail. 2 Dimeric and higher-molecular-weight complexes of FAP have been described.

Gene Expression Profiling of Alcoholic Liver Disease in the Baboon (Papio hamadryas) and Human Liver

“…No co-localization was observed with the stem cell markers CD117 (c-kit) and CD34; a B-cell marker (CD 19); a marker for quiescent stellate cells (synaptophysin); or for activated stellate cells 15 fibroblast activation protein (data not shown).…”

“…Slides from Ϫ20°C were prewarmed at 37°C for 15 minutes before blocking, staining, and imaging as described previously 15,16 using the reagents listed in Table 2. Goat anti-rabbit IgG-Alexa Fluor 594 and goat anti-mouse IgG-Alexa Fluor 488 (Molecular Probes, Eugene, OR) secondary antibodies (1:400 dilution) were used for detection.…”

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 + T cells

“…Fibroblast activation protein-α (FAP) is a marker of stromal cells that was originally described in human adenocarcinomas and at sites of wound healing and subsequently was demonstrated also at sites of chronic inflammation and immune privilege (14)(15)(16)(17). Whereas FAP −/− mice are phenotypically indistinct from wild-type mice (18), the stromal cell that expresses FAP mediates immune suppression in the tumor microenvironment (19,20) and maintains skeletal muscle mass and hematopoiesis (21,22).…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…FAP␣ is strongly expressed by reactive stromal fibroblasts within the stroma of the majority of human epithelial tumors but not in carcinoma cells (133). It is also expressed on reactive fibroblasts in granulation tissue of healing wounds, on stellate cells at the tissue remodeling interface in cirrhosis (134), and in lung tissue in idiopathic pulmonary fibrosis (135). Due to this rather "disease-specific" expression, FAP␣ is an attractive therapeutic target.…”