Fibroblast activation protein drives tumor metastasis via a protease-independent role in invadopodia stabilization.

During metastasis, tumor cells invade through the basement membrane and intravasate into blood vessels and then extravasate into distant organs to establish metastases. Here, we report a critical role of a transmembrane serine protease fibroblast activation protein (FAP) in tumor metastasis. Expression of FAP and TWIST1, a metastasis driver, is significantly correlated in several types of human carcinomas, and FAP is required for TWIST1-induced breast cancer metastasis to the lung.

Suppression of tumor growth in mice by rationally designed pseudopeptide inhibitors of fibroblast activation protein and prolyl oligopeptidase.

Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth.

Targeting inhibition of fibroblast activation protein-α and prolyl oligopeptidase activities on cells common to metastatic tumor microenvironments.

Fibroblast activation protein (FAP), a membrane prolyl-specific proteinase with both dipeptidase and endopeptidase activities, is overexpressed by reactive stromal fibroblasts during epithelial-derived cancer growth. FAP digests extracellular matrix as tissue is remodeled during cancer expansion and may also promote an immunotolerant tumor microenvironment. Recent studies suggest that nonspecific FAP inhibitors suppress human cancer xenografts in mouse models.

Using substrate specificity of antiplasmin-cleaving enzyme for fibroblast activation protein inhibitor design.

Circulating antiplasmin-cleaving enzyme (APCE), a prolyl-specific serine proteinase, is essentially identical to membrane-inserted fibroblast activation protein (FAP) that is transiently expressed during epithelial-derived cancer growth. Human precursive alpha(2)-antiplasmin (Met-alpha(2)AP), the only known physiologic substrate for APCE, is cleaved N-terminally to Asn-alpha(2)AP that is rapidly cross-linked to fibrin and protects it from digestion by plasmin. Identifying a specific inhibitor of APCE/FAP continues to be intensely pursued.

Phase II trial of single agent Val-boroPro (Talabostat) inhibiting Fibroblast Activation Protein in patients with metastatic colorectal cancer.

Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer.

Methods: Patients with metastatic colorectal cancer who had previously received systemic chemotherapies were treated with single agent Val-boroPro 200 microg p.

The effect of a single nucleotide polymorphism on human alpha 2-antiplasmin activity.

The primary inhibitor of plasmin, alpha(2)-antiplasmin (alpha(2)AP), is secreted by the liver into plasma with Met as the amino-terminus. During circulation, Met-alpha(2)AP is cleaved by antiplasmin-cleaving enzyme (APCE), yielding Asn-alpha(2)AP, which is crosslinked into fibrin approximately 13 times faster than Met-alpha(2)AP. The Met-alpha(2)AP gene codes for either Arg or Trp as the sixth amino acid, with both polymorphic forms found in human plasma samples.

Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types I, III, and IV.

The circulating enzyme, alpha2-antiplasmin cleaving enzyme (APCE), has very similar sequence homology and proteolytic specificity as fibroblast activation protein (FAP), a membrane-bound proteinase. FAP is expressed on activated fibroblasts associated with rapid tissue growth as in embryogenesis, wound healing, and epithelial-derived malignancies, but not in normal tissues. Its presence on stroma suggests that FAP functions to remodel extracellular matrix (ECM) during neoplastic growth.

Antiplasmin-cleaving enzyme is a soluble form of fibroblast activation protein.

Circulating antiplasmin-cleaving enzyme (APCE) has a role in fibrinolysis and appears structurally similar to fibroblast activation protein (FAP), a cell-surface proteinase that promotes invasiveness of certain epithelial cancers. To explore this potential relationship, we performed comparative structure/function analyses of the 2 enzymes. APCE from human plasma and recombinant FAP (rFAP) exhibited identical pH optima of 7.

Alpha2-antiplasmin: potential therapeutic roles in fibrin survival and removal.

Alpha2-antiplasmin (alpha2AP) is the primary inhibitor of plasmin, a proteinase that digests fibrin, the main component of blood clots. Two forms of alpha2AP circulate in human plasma: a 464-residue protein with methionine as the amino-terminus (Met-alpha2AP) and an N-terminally-shortened 452-residue form with asparagine as the amino-terminus (Asn-alpha2AP). Human plasma alpha2AP concentration is 1 micro M and consists of approximately 30% Met-alpha2AP and approximately 70% Asn-alpha2AP.

A novel plasma proteinase potentiates alpha2-antiplasmin inhibition of fibrin digestion.

Human alpha2-antiplasmin (alpha2AP), also known as alpha2-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms of alpha2AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-alpha2AP, and a 452-residue version with Asn as the N-terminus, Asn-alpha2AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-alpha2AP to yield Asn-alpha2AP and have named it antiplasmin-cleaving enzyme (APCE).