Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

Abstract

Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro-tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP's basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP.

Figure 1. FAP expression in healthy adult mouse

Genetically engineered mice with luciferase reporter knock-in at both FAP alleles were administered luciferin ten minutes before euthanasia and organs harvested for imaging. Results indicate that FAP is expressed in skin, bone, pancreas, and at very low levels in the kidney. (Data generated by Leslie Hopper and Michele Jacob)

Figure 2. Potential regulatory networks of FAP transcription

Multiple environmental and soluble factors have been observed to alter FAP expression, though detailed mechanistic pathways for many of them are unknown. The best characterized is TGFβ activation of SMAD3, which binds directly to the FAP promoter. A2BR: adenosine 2B receptor. ADO: adenosine. EE: estrogens. EGR-1: early growth response protein 1. ERα: estrogen receptor alpha. ERK1/2: extracellular signal-related kinases 1 and 2. FAP: fibroblast activation protein. GPR30: g-protein coupled receptor 30. hTERT: human telomerase reverse transcriptase. IL-1β: interleukin 1 beta. LPS: lipopolysaccharide. miR: microRNA. PGRN: progranulin. PTEN: phosphatase and tensin homolog. SiNW: silicon nanowires. SMAD3: mothers against decapentaplegic homolog 3. STAT3: Signal transducer and activator of transcription 3. TGFβ: transforming growth factor beta. TGFβR: TGFβ receptor. TLR4: toll-like receptor 4. TNFα: tumor necrosis factor alpha. UV: ultraviolet radiation.

Figure 3. Selected mechanisms of action for FAP in the TME

Shown are some of the best-elucidated pathways by which FAP promotes tumor growth. FAP can be expressed by macrophages, tumor cells, and tumor-promoting mesenchymal stromal cells, and it exerts effects though both enzymatic and non-enzymatic means. CCL2: (MCP1) c-c motif chemokine ligand 2. Col I: type I collagen. FAK: focal adhesion kinase. FAP: fibroblast activation protein. hFGF-21: human fibroblast growth factor 21. MMPs: matrix metalloproteinases. NPY: neuropeptide Y. PI3K: phosphoinositide 3-kinase. PTEN: phosphatase and tensin homolog. RhoA: ras homolog gene family member A. SR-A: (MSR1) class A macrophage scavenger receptor. uPAR: urokinase plasminogen activator receptor.