Fibroblast Activation Protein (FAP) is a specialized protease enzyme found on the surface of fibroblasts. Fibroblasts are the primary cells responsible for maintaining tissue structure by producing the extracellular matrix. While essential for normal tissue maintenance and repair, FAP expression is virtually absent in healthy adult tissues but becomes dramatically upregulated in pathological conditions.
The Molecular Role of Fibroblast Activation Protein
FAP is categorized as a serine protease, a class of enzymes that cleave other proteins using a serine amino acid residue at their active site. It is closely related to the dipeptidyl peptidase-4 (DPP4) family. This enzyme exhibits a dual function: dipeptidyl peptidase activity and endopeptidase activity, sometimes referred to as gelatinase activity.
The dipeptidyl peptidase action allows FAP to sequentially remove two amino acids from the end of a protein chain, specifically following a proline residue. Its endopeptidase activity enables FAP to cut proteins internally, including components of the extracellular matrix (ECM) like denatured collagen. This proteolytic action is fundamental to temporary tissue remodeling, such as during wound healing, where activated fibroblasts transiently express FAP to reorganize the ECM. Once healing is complete, FAP expression subsides to low or undetectable levels.
FAP’s Role in the Tumor Microenvironment
In the context of cancer, fibroblasts become persistently activated, transforming into what are known as Cancer-Associated Fibroblasts (CAFs), which are marked by high FAP expression. These FAP-positive CAFs are a defining feature of the tumor microenvironment (TME), the complex support structure surrounding tumor cells, and are present in the stroma of over 90% of common epithelial cancers, including pancreatic, breast, and colorectal tumors. The high concentration of FAP at the tumor site has been linked to a more aggressive disease and a poorer prognosis for patients.
FAP activity significantly contributes to the pathological remodeling of the ECM, which is a hallmark of the TME. By breaking down and reshaping the dense collagen scaffold, FAP-expressing CAFs create channels that facilitate tumor cell invasion and metastasis. This modification of the physical environment allows cancer cells to escape the primary tumor mass and spread throughout the body.
The CAFs also release a variety of growth factors, chemokines, and cytokines that directly support the proliferation and survival of the adjacent cancer cells. FAP-expressing CAFs also play a role in helping the tumor evade destruction by the immune system. The proteolytic activity of FAP suppresses local immune responses within the TME, creating an environment where immune cells are less effective at recognizing and eliminating cancer cells. This immune suppression allows the tumor to grow unchecked.
Linking FAP to Organ Scarring and Fibrosis
FAP’s expression is a significant indicator of chronic diseases characterized by uncontrolled scarring, a process called fibrosis. In these non-cancerous settings, the temporary activation of fibroblasts seen in normal wound healing becomes a persistent, pathological state. Examples include liver cirrhosis, where the liver stiffens and fails, and idiopathic pulmonary fibrosis, which causes irreversible scarring in the lungs.
In fibrosis, FAP-positive fibroblasts drive the excessive and sustained production and deposition of collagen and other ECM components. This pathological accumulation causes the affected organ tissue to become stiff, rigid, and non-functional. The FAP enzyme contributes by altering the delicate balance of matrix synthesis and degradation, leading to structural failure. Unlike its role in cancer, FAP’s activity in fibrosis contributes to the hardening and contraction of the tissue, ultimately destroying the organ’s architecture and function.
FAP as a Diagnostic and Therapeutic Target
The highly selective expression pattern of FAP—abundant in disease but largely absent in healthy adult tissues—makes it an attractive target for clinical intervention. This specificity allows researchers and clinicians to target pathological cells while sparing healthy ones, minimizing side effects.
One of the most promising diagnostic applications is the use of FAP Inhibitor (FAPI) PET scans. These scans use a small molecule that binds specifically to the FAP enzyme, which is then tagged with a radioactive tracer. When injected into a patient, this FAPI tracer lights up FAP-expressing cells in tumors or areas of fibrosis throughout the body with high contrast. FAPI PET imaging has shown advantages over traditional scans in certain cancers, offering improved precision for initial staging, detection of recurrence, and monitoring of treatment response.
In therapy, FAP is being explored as a molecular delivery system, a concept known as theranostics. This approach involves attaching a therapeutic payload, such as chemotherapy drugs or radiation-emitting isotopes, to the FAP-targeting molecule. The FAP-targeting agent then delivers the treatment directly to the diseased fibroblasts and the surrounding tissue. This allows for a high concentration of the destructive agent at the site of disease while reducing systemic exposure and damage to healthy cells.