Proteolytic degradation of extracellular matrix (ECM) components during tissue remodeling plays a pivotal role in normal and pathological processes including wound healing, inflammation, tumor invasion, and metastasis. Proteolytic enzymes in tumors may activate or release growth factors from the ECM or act directly on the ECM itself, thereby facilitating angiogenesis or tumor cell migration. Fibroblast activation protein (FAP) is a cell surface antigen of reactive tumor stromal fibroblasts found in epithelial cancers and in granulation tissue during wound healing. It is absent from most normal adult human tissues. FAP is conserved throughout chordate evolution, with homologues in mouse and Xenopus laevis, whose expression correlates with tissue remodeling events. Using recombinant and purified natural FAP, we show that FAP has both dipeptidyl peptidase activity and a collagenolytic activity capable of degrading gelatin and type I collagen; by sequence, FAP belongs to the serine protease family rather than the matrix metalloprotease family. Mutation of the putative catalytic serine residue of FAP to alanine abolishes both enzymatic activities. Consistent with its in vivo expression pattern determined by immunohistochemistry, FAP enzyme activity was detected by an immunocapture assay in human cancerous tissues but not in matched normal tissues. This study demonstrates that FAP is present as an active cell surface-bound collagenase in epithelial tumor stroma and opens up investigation into physiological substrates of its novel, tumorassociated dipeptidyl peptidase activity.

The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.

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.