Fibroblasts are common cells that act as the architects of our connective tissues. They produce and organize the extracellular matrix, a network of proteins like collagen that provides structural support to tissues. A specific protein found on the surface of some fibroblasts, known as Fibroblast Activation Protein (FAP), has attracted scientific attention. FAP-expressing fibroblasts are an area of research because of their involvement in processes ranging from tissue repair to the progression of several diseases.
The Basics of Fibroblasts and FAP
Fibroblasts are responsible for creating the scaffolding that gives tissues their shape and strength. During an injury, these cells become active, migrating to the damaged area to produce new matrix components and help seal the wound. This process is a regulated part of healing, demonstrating the fibroblast’s role in tissue maintenance.
Fibroblast Activation Protein is a molecule that appears on the surface of these fibroblasts under certain conditions. It is a type II transmembrane serine protease, meaning it is anchored to the cell’s membrane and functions like a pair of molecular scissors. Its job is to cut other proteins, an enzymatic activity that allows it to modify the immediate environment around the cell.
This ability to alter the extracellular matrix and other signaling molecules is why FAP is influential. Its enzymatic capability is highly regulated in healthy tissues but can become dysregulated in various disease states, leading to significant changes in tissue structure and function.
FAP Expression in Normal and Diseased Tissues
The presence of Fibroblast Activation Protein in the body is highly conditional. In most healthy adult tissues, FAP is expressed at very low or undetectable levels. Its appearance is temporary and localized, showing up in fibroblasts during wound healing to remodel damaged tissue before disappearing once the repair is complete.
This pattern changes in the context of disease, where FAP expression becomes sustained. It is found in tissues affected by fibrosis, a condition involving excessive scar tissue in organs like the liver, lungs, and kidneys. FAP is also present in the inflamed joints of individuals with rheumatoid arthritis.
The most prominent upregulation of FAP occurs within the stroma, or connective tissue, of many cancers. It is overexpressed in the stroma of up to 90% of epithelial carcinomas, including breast, colon, pancreas, and lung cancers. In these tissues, FAP becomes a marker for a population of fibroblasts known as cancer-associated fibroblasts (CAFs).
FAP’s Influence on Cancer Progression
FAP-positive CAFs are not passive bystanders; they actively contribute to the growth and spread of cancer. These cells create a supportive setting for tumor cells by engaging in multiple activities that fuel disease progression.
One of the primary ways CAFs assist tumors is by remodeling the extracellular matrix. The enzymatic function of FAP degrades the existing tissue scaffolding, which clears a path for cancer cells to invade surrounding tissues and metastasize to other parts of the body. This creates a microenvironment that is more permissive for tumor expansion.
These fibroblasts also promote angiogenesis, the formation of new blood vessels that tumors need to grow. By secreting growth factors, CAFs encourage a blood supply that delivers oxygen and nutrients to the tumor. They also contribute to an immunosuppressive environment by releasing signals that interfere with the ability of immune cells to recognize and attack the cancer, helping tumors evade the immune system.
The prognostic significance of FAP expression can vary by cancer type. In many cancers, such as gastric and colon cancer, high levels of FAP correlate with a worse outcome. However, in some cases, like certain breast cancers, FAP expression has been linked to longer survival, highlighting the complexity of its role and its context-dependent function.
Targeting FAP for Diagnosis and Treatment
FAP’s expression pattern makes it an attractive target for medical applications. Scientists are exploring ways to use this protein to both diagnose and treat diseases, particularly cancer, by developing interventions that leave healthy cells unharmed.
For diagnosis, researchers are developing imaging agents that bind to FAP. These agents can be linked to radioactive molecules, allowing doctors to visualize tumors or areas of fibrosis with imaging techniques like PET scans. This approach, known as theranostics, combines diagnosis and therapy, as the same targeting molecule could deliver treatment.
Several therapeutic strategies targeting FAP are under investigation. These innovative approaches hold the potential to offer new treatments for cancer and other fibrotic diseases.
- FAP inhibitors are drugs designed to block the protein’s enzymatic activity and prevent tissue remodeling.
- FAP-targeted antibodies can deliver toxins or chemotherapy drugs directly to CAFs, destroying them and the supportive environment they create.
- Vaccines can train the immune system to recognize and attack FAP-positive cells.
- Engineered immune cells, known as CAR-T cells, can be programmed to seek out and eliminate cells with FAP on their surface.