Fibroblast activation protein-α and dipeptidyl peptidase IV (CD26): Cell-surface proteases that activate cell signaling and are potential targets for cancer therapy
Introduction
The post-prolyl peptidases are a class of enzymes that are inducible, active on the cell surface or in extracellular fluids, and uniquely capable of cleaving the Pro-XAA bond. These enzymes have important roles in cancer (for reviews see (Chen and Kelly, 2003, Chen et al., 2003, Rosenblum and Kozarich, 2003, Busek et al., 2004). Through their enzymatic activities, the post-prolyl peptidases modify bioactive peptides and change cellular functions. This group of enzymes includes quiescent cell proline amino peptidase, prolyl carboxy-peptidase, prolyl endopeptidase, dipeptidyl peptidase 6, dipeptidyl peptidase 8, dipeptidyl peptidase 9, attractin, dipeptidyl peptidase II, and dipeptidyl peptidase IV-β (see Chen et al., 2003). But, the best studied of the post-prolyl peptidases is the cell surface serine protease, dipeptidyl peptidase IV (DPPIV or CD26). Recent studies have shown the importance of DPPIV in regulating tumor cell behavior and function (Bauvois, 2004). This review is focused on fibroblast activation protein-α (FAP-α, also known as “seprase”), which is another post-prolyl peptidase and cell surface serine protease that is closely related to DPPIV. FAP-α has important roles in tumor biology that are just beginning to be understood. Clues provided by the relatively large volume of work done on DPPIV have yielded important insights into the potential functions of FAP-α and examples of these are highlighted throughout the text. Indeed, FAP-α and DPPIV may function coordinately to regulate tumor cell behavior and both enzymes are appealing targets for therapies designed to eradicate cancer cells.
Section snippets
Aberrant expression of fibroblast activation protein-α in the tumor microenvironment
FAP-α is a cell-surface serine protease that was originally identified as an inducible antigen expressed on reactive stromal fibroblasts (Rettig et al., 1988, Rettig et al., 1993, Garin-Chesa et al., 1990). FAP-α was independently identified by Chen and co-workers as a 170-kDa membrane-associated gelatinase that is expressed by aggressive melanoma cell lines and transformed chicken embryo fibroblasts (Aoyama and Chen, 1990, Kelly et al., 1994, Monsky et al., 1994). These workers called this
FAP-α: a member of the post prolyl peptidase family of enzymes known to regulate cell behaviors
The post-prolyl peptidases are uniquely capable of cleaving the prolyl peptide bond Pro-XAA. This emerging group of prolyl oligopeptidases comprises a family with three main subdivisions as defined by sequence homology (Barrett and Rawlings, 1992, Sedo and Malik, 2001, Chen et al., 2003, Rosenblum and Kozarich, 2003). Prolyl endopeptidase is prototypical of the S9a family and acylaminoacyl peptidase of the S9c family. FAP-α and DPPIV (also called CD26) belong to the S9b peptidase family and are
FAP-α as a tumor promoter
To investigate the role of FAP-α in breast cancer, we used human breast cancer cell lines that normally express FAP-α (MDA-MB 435 and MDA-MB 436). Anti-sense suppression of FAP-α expression made these cells sensitive to serum starvation, while control transfectants with high levels of FAP-α expression grew well even in the absence of serum (Goodman et al., 2003). Therefore, the breast cancer cells with high FAP-α levels are less dependent on exogenous serum factors for growth and have gained
FAP-α signaling – a new frontier
There is an obvious incongruence between FAP-α function in tumor promotion obtained by our group and Cheng's group and the evidence of FAP-α function as a tumor suppressor obtained by Houghton's group. We propose that FAP-α expression has a profound effect on cells that do not normally express FAP-α, and that the context in which FAP-α is expressed determines the biological response to FAP-α (promotion or inhibition of growth). A model that explains all the findings obtained thus far is one
FAP-α provides target specificity to anti-tumor agents
FAP-α is induced in tumors, is not found on normal adult tissues, and is physically attached to tumor cells. These properties make it an appealing molecule to provide target specificity for reagents designed to kill tumor cells. Phase I trials and a limited phase II trial have been conducted with an unconjugated, humanized version of monoclonal antibody F19 to FAP-α called sibrotuzumab (Hofheinz et al., 2003, Scott et al., 2003, Kloft et al., 2004). Sibrotuzumab is well-tolerated, safe and a
Conclusions
FAP-α-expression results in profound behavioral changes in tumor cells that are mediated both by the protease activity of FAP-α and by the formation of FAP-α complexes with proteolytic, adhesive, and signaling capabilities. FAP-α expression has significant consequences for host cells. Angiogenesis is stimulated and anti-tumor activity of the immune system is suppressed. Future work will elucidate the roles of the protease activity and complex formation in mediating the promotion or suppression
Acknowledgement
The author thanks Randy Haun and Ralph D. Sanderson at the University of Arkansas for Medical Sciences, Little Rock, AR and Barbara L. Parsons at the National Center for Toxicological Research, Jefferson, AR for critical review of the manuscript. Jonathan Cheng, Fox Chase Cancer, Philadelphia, PA supplied Fig. 1. The author thanks Alan N. Houghton, Memorial Sloan Kettering Cancer Center, NY, for helpful discussions regarding tumor suppression versus tumor promotion by FAP-α.
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