The gene FSP1, located on chromosome 1, holds the blueprint for a protein with a complex and dual nature. This protein, S100A4, is a component of many cells and participates in fundamental life processes. However, it has also captured the attention of medical researchers for its significant involvement in various disease states. Understanding this protein’s function offers a window into the balance between health and disease at a cellular level.
The S100A4 Protein and Its Cellular Functions
The gene FSP1 is more commonly recognized by the protein it produces, S100A4. This protein belongs to a larger family of S100 proteins, characterized by their ability to bind calcium. The binding of calcium ions acts like a switch, causing the S100A4 protein to change its shape. This change allows it to interact with and regulate the activity of other proteins inside the cell.
One of the primary roles of S100A4 in a healthy cell is managing the internal scaffolding, known as the cytoskeleton. It interacts with structural proteins, such as non-muscle myosin IIA, to control their assembly and disassembly. This regulation is important for determining a cell’s shape and enabling its movement, a process called cell motility. S100A4’s influence on the cytoskeleton allows cells to move in a directed manner, which is part of processes like wound healing.
Beyond motility, S100A4 is involved in cell cycle progression and differentiation, the processes that guide how a cell grows, divides, or becomes specialized. It can be found in both the cytoplasm and the nucleus of a wide variety of cells, from immune cells to fibroblasts. By influencing these basic cellular activities, the S100A4 protein contributes to the routine maintenance and function of tissues.
Connection to Cancer Progression
The normal functions of the S100A4 protein can be exploited by cancer cells to promote their survival and spread. High levels of S100A4 are frequently observed in aggressive tumors and are linked with a greater likelihood of metastasis, the process where cancer cells spread from their original site to other parts of the body. The protein’s ability to enhance cell motility is hijacked, giving cancer cells the mobility to break away from the primary tumor, enter the bloodstream, and invade distant tissues.
A process in metastasis that S100A4 facilitates is the epithelial-mesenchymal transition (EMT). EMT is a program where stationary epithelial cells, which are bound to their neighbors, transform into mobile mesenchymal cells. S100A4 is a known driver of this transition, partly by causing the downregulation of proteins like E-cadherin that help cells adhere. This loss of adhesion allows cancer cells to detach and begin their journey to other organs.
Once secreted by tumor or surrounding cells, S100A4 can also act on the tumor’s environment to support its growth. It can stimulate angiogenesis, the formation of new blood vessels, which tumors need to supply themselves with nutrients and oxygen. The protein synergizes with other growth factors to promote the migration of endothelial cells, the building blocks of blood vessels. By driving these processes, S100A4 becomes a multifaceted contributor to cancer progression.
Involvement in Fibrosis and Inflammation
The influence of FSP1/S100A4 extends beyond cancer to non-cancerous conditions, notably fibrosis and chronic inflammation. Fibrosis is the excessive formation of scar tissue in an organ, which can impair its function and lead to organ failure. S100A4 is a recognized player in fibrosis in organs such as the kidneys, lungs, liver, and heart. It contributes to this process by promoting the activation of fibroblasts, the cells responsible for producing scar tissue components.
In these fibrotic diseases, S100A4 is often released at sites of injury and inflammation. Once in the extracellular space, it can act as a signal that triggers further inflammatory responses and promotes the remodeling of the extracellular matrix. This creates a pro-fibrotic environment where scar tissue deposition is favored over normal tissue repair. Elevated levels of S100A4 in the blood have been correlated with the severity of disease in several fibrotic conditions.
The protein is also implicated in chronic inflammatory diseases like rheumatoid arthritis. In this context, S100A4 can enhance the migration of immune cells, such as macrophages and neutrophils, to sites of inflammation, like the joints. This recruitment of inflammatory cells contributes to the persistent inflammation and tissue damage characteristic of these disorders. S100A4 can also activate specific cell surface receptors on immune cells, leading to an increased inflammatory response.
Therapeutic and Diagnostic Potential
The association of high S100A4 levels with disease progression has positioned it as a biomarker. A biomarker is a measurable indicator of a biological state or condition. Measuring the amount of S100A4 in patient tissue or blood samples can help doctors assess disease. For instance, elevated S100A4 levels can indicate a higher risk of metastasis in cancers like colorectal, breast, and stomach cancer, helping to inform prognosis and treatment decisions.
Beyond its use for diagnosis, S100A4 is being investigated as a therapeutic target. The goal is to develop drugs that can block the function of the S100A4 protein or inhibit its production. Researchers have identified compounds, such as niclosamide, that can repress the gene’s activity, leading to reduced cell migration and lower metastasis in preclinical models of colon cancer. This strategy aims to restrict the invasive capabilities of cancer cells.
This therapeutic approach is not limited to cancer. Since S100A4 is a factor in fibrosis, developing inhibitors could also offer a new way to treat fibrotic diseases by reducing the activity of scar-producing cells. Strategies being explored include neutralizing antibodies that block extracellular S100A4 and small molecules that interfere with its interaction with other proteins. These efforts could lead to treatments that halt or reverse the progression of both cancer and fibrosis by targeting a shared molecular driver.