Fibroblast Activation Protein (FAP) is a protein that has garnered considerable scientific attention. It is involved in various biological processes, with implications for understanding both healthy bodily functions and disease development.
Understanding Fibroblast Activation Protein
Fibroblast Activation Protein (FAP) is an enzyme found on the surface of certain cells. It is predominantly expressed by activated fibroblasts, which are cells involved in connective tissue. FAP’s enzymatic function involves cleaving specific proteins, often at sequences containing a glycine-proline bond. This proteolytic activity breaks down other proteins.
FAP exists as a 170 kDa homodimer, meaning two identical FAP units are linked together to form an active enzyme. Its structure includes a short cytoplasmic tail, a transmembrane region, and a large extracellular part where its enzymatic activity occurs. While FAP is primarily membrane-bound, a soluble form can also be found in blood plasma and tissue fluid.
FAP’s Role in Healthy Tissues
In healthy adult tissues, FAP expression is generally very low. However, it plays a role in specific physiological processes, particularly tissue remodeling and repair. FAP is strongly induced during wound healing, where it contributes to scar formation and the overall repair process. This involvement highlights its function in restoring tissue integrity after injury.
FAP is also expressed during embryonic development, suggesting a role in normal growth and tissue formation. In adults, low levels of FAP have been detected in certain cells like multipotent bone marrow stromal cells (BM-MSCs), where its presence is linked to their ability to migrate to injured tissues, a process important for regeneration. FAP’s ability to cleave alpha-2 anti-plasmin, an inhibitor of plasmin, can enhance clotting during tissue repair, contributing to the body’s natural response to injury.
FAP’s Involvement in Disease
While FAP plays a role in healthy tissue repair, its activity becomes significantly elevated in various disease states. It is highly expressed in the reactive stromal fibroblasts of over 90% of human epithelial cancers. Within the tumor microenvironment, FAP-positive cancer-associated fibroblasts (CAFs) contribute to tumor growth, invasion, and metastasis. These CAFs can influence extracellular matrix remodeling, angiogenesis (new blood vessel formation), and suppress the immune system, allowing tumors to evade detection.
FAP’s pro-tumorigenic effects include promoting cell proliferation, migration, and invasion. It can directly affect cell motility and migration through its enzymatic activity. FAP is also implicated in fibrotic diseases, which are characterized by excessive scarring and tissue hardening. Elevated FAP levels have been reported in fibrotic conditions affecting organs such as the liver, lungs, and colon, contributing to uncontrolled scarring that can lead to organ failure. FAP also participates in chronic inflammation, where its expression can be increased by inflammatory cytokines.
Targeting FAP for Medical Applications
The selective and high expression of FAP in diseased tissues, particularly in cancer and fibrosis, makes it an attractive target for medical applications. For diagnostic imaging, small molecule FAP inhibitors (FAPIs) can be radiolabeled and used in Positron Emission Tomography (PET) scans to detect FAP-rich areas in the body. This approach has shown promise in visualizing various tumors, sometimes demonstrating superiority over traditional imaging agents like 18F-FDG.
Beyond diagnostics, FAP is being explored for therapeutic strategies. One approach involves inhibiting FAP’s enzymatic activity to disrupt its pro-disease functions. Another strategy uses FAP to carry therapeutic agents directly to diseased tissues. This includes FAP-targeted radioligand therapy (RLT), where radioactive isotopes are attached to FAP-targeting molecules, delivering localized radiation to FAP-expressing cells and minimizing damage to healthy tissues. Research is ongoing with FAPI-based radiopharmaceuticals, including those labeled with Lutetium-177 or Yttrium-90, showing potential for controlling disease progression in advanced metastatic tumors. Prodrugs activated specifically by FAP are also being developed to enhance tumor killing while reducing systemic side effects.