The role of fibroblast activation protein in health and malignancy
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The role of fibroblast activation protein in health and malignancy Allison A. Fitzgerald 1
&
Louis M. Weiner 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Fibroblast activation protein-α (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions including fibrosis, arthritis, and cancer. Across most cancer types, elevated FAP is associated with worse clinical outcomes. Despite the clear association between FAP and disease severity, the biological reasons underlying these clinical observations remain unclear. Here we review basic FAP biology and FAP’s role in non-oncologic and oncologic disease. We further explore how FAP may worsen clinical outcomes via its effects on extracellular matrix remodeling, intracellular signaling regulation, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. Lastly, we discuss the potential to exploit FAP biology to improve clinical outcomes. Keywords Fibroblast activation protein (FAP) . Fibroblasts . Stroma . Invasion
1 Introduction Fibroblast activation protein-α (FAP) was first described in 1986 by Wolfgang Rettig as a cell surface antigen expressed on the reactive stromal fibroblasts of epithelial cancers, most soft tissue sarcomas, granulation tissue of wound healing, and certain fetal mesenchymal fibroblasts. Conversely, it was not expressed in normal fibroblasts, normal or malignant epithelial cells, or the stroma of benign epithelial tumors. Hence, it was named “fibroblast activation protein.” In 1990, Atsuko Aoyama identified a dimeric 170 kDa membrane-bound gelatinase on the invadopodia of the human melanoma cell line LOX, which was subsequently named “seprase” for surface-expressed protease [1, 2]. Cloning and sequence analysis later revealed FAP and seprase to be identical [3, 4]. Unfortunately, both names are only partially accurate. Subsequent research went on to demonstrate that FAP could be expressed in non-fibroblast cell types, such as epithelial tumors [5–7], melanocytes and melanoma [2, 8], and recently macrophages [9]. Seprase also is not entirely accurate as FAP can be shed from the plasma membrane forming a soluble FAP, which is referred to as α2-antiplasmin cleaving enzyme (APCE) [10]. Hence, it is not restricted to the cell surface. In * Louis M. Weiner [email protected] 1
Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3870 Reservoir Road NW, Washington, DC 20057, USA
any event, the name “fibroblast activation protein-a” and the symbol “FAP” predominate in the literature and are the official name and symbol listed in NCBI Gene and, consequently, will be used throughout this review.
2 FAP protein structure and function 2.1 Enzymatic activity FAP is a 97-kDa type II transmembrane serine protease. FAP is a member of the prolyl peptidase family, which also contains dipeptidyl peptidase IV (DPPIV, CD26), DPP7 (DPP II, quiescent cell proline dipeptidase), DPP8, DPP9, and prolyl carboxypepti
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