Fibroblast Activation Protein (FAP) is a protein on the outer surface of cells known as fibroblasts. These fibroblasts become particularly active during periods of tissue remodeling. The expression of FAP is minimal in most healthy adult tissues, but its levels increase at sites where tissue is actively repaired, such as in wound healing, fetal development, and within diseased tissues. This selective expression has made FAP a subject of scientific interest.
The Function of FAP in Disease Progression
FAP operates as an enzyme called a serine protease. Its primary job is to modify the extracellular matrix, which is the structural scaffolding that holds cells and tissues together. The extracellular matrix provides support and organization for cells. In healthy tissues, this process is tightly controlled to maintain normal tissue function and architecture.
In diseases such as cancer and fibrosis, the behavior of FAP changes significantly. Fibroblasts in these environments become “activated” and begin to produce FAP in large quantities. This overproduction leads to excessive breakdown of the extracellular matrix. In cancer, these FAP-expressing cells are referred to as cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment.
The enzymatic activity of FAP has direct consequences for cancer progression. By degrading components of the extracellular matrix, FAP helps to dismantle the physical barriers that would normally contain a tumor. This breakdown creates pathways that allow cancer cells to migrate from their original location and invade adjacent healthy tissues. This process is a foundational step in metastasis, the spread of cancer to distant parts of the body.
Beyond cancer, FAP is a contributor to fibrosis, which is the excessive formation of scar tissue in organs. In conditions like liver cirrhosis or idiopathic pulmonary fibrosis, activated fibroblasts drive the disease by depositing large amounts of collagen. FAP is involved in this process, contributing to the stiffening and loss of function in affected organs like the heart, lungs, and liver.
Targeting FAP for Cancer Treatment
The discovery of FAP’s prevalence in the tumor microenvironment has led to the development of therapies designed to target it. Because FAP is abundant on cancer-associated fibroblasts but largely absent from healthy cells, treatments can be directed specifically at the tumor site. This approach can reduce damage to the rest of the body by exploiting the difference in FAP expression.
One approach involves the use of FAP inhibitors. These are small molecule drugs designed to enter the tumor microenvironment and block the enzymatic function of the FAP protein. By inhibiting FAP’s ability to act as a protease, these drugs prevent it from breaking down the extracellular matrix. The goal is to reinforce the tissue scaffolding around the tumor, thereby impeding the ability of cancer cells to metastasize.
Another therapeutic strategy is the use of antibody-drug conjugates (ADCs). ADCs are complex molecules that consist of an antibody connected to a powerful chemotherapy drug. The antibody component is engineered to recognize and bind to the FAP protein on cancer-associated fibroblasts. Once attached, the entire ADC is absorbed by the fibroblast, which then releases the toxic drug payload inside the targeted cell, leading to its destruction.
A third strategy is CAR-T cell therapy. This form of immunotherapy involves harvesting a patient’s own T-cells and genetically modifying them. The engineered T-cells are equipped with a chimeric antigen receptor (CAR) that specifically recognizes the FAP protein. These modified cells are then infused back into the patient, where they actively seek out and destroy cells expressing FAP, including the cancer-associated fibroblasts.
FAP in Medical Imaging and Theranostics
The selective presence of FAP on tumors has made it a valuable biomarker for diagnostic purposes. Its high concentration in the tumor microenvironment, contrasted with its near absence in healthy tissues, allows for highly specific imaging of cancerous growths. This property helps visualize tumors with greater clarity than many conventional methods.
This imaging is accomplished by attaching a radioactive tracer to a molecule designed to bind to FAP. This compound travels through the bloodstream and accumulates at sites where FAP is present. Medical imaging techniques, such as positron emission tomography (PET) scans, can then detect the radiation emitted by the tracer. The result is a detailed image that highlights the precise location and extent of tumors.
This application of FAP has also given rise to theranostics, a term that combines “therapeutics” and “diagnostics.” This approach uses a single targeting molecule for both diagnosis and treatment. The process begins with a diagnostic scan, where a FAP-targeting molecule is linked to a low-dose radioactive isotope for imaging. This initial step confirms that the patient’s tumor expresses FAP and is a suitable candidate for this therapy.
Following the diagnostic scan, the same FAP-targeting molecule is used again, but this time it is armed with a more potent, therapeutic radioactive isotope. When this compound is administered, it travels to the FAP-expressing cells and delivers a highly localized dose of radiation. This targeted radiotherapy kills the cancer-associated fibroblasts and nearby cancer cells while minimizing radiation exposure to healthy tissues.