The S100A4 protein is a small, calcium-binding protein found across various body tissues. It participates in numerous cellular functions, influencing how cells behave and interact.
What is S100A4?
S100A4 belongs to the S100 family of proteins, characterized by their small size and ability to bind calcium. The name “S100” signifies their solubility in 100% saturated ammonium sulfate at a neutral pH.
Structurally, S100A4 typically exists as a homodimer, composed of two identical protein units. Each unit contains two EF-hand motifs responsible for binding calcium. Calcium binding induces a significant change in S100A4’s shape, exposing a hydrophobic surface that allows it to interact with other target proteins. This conformational shift is fundamental to its diverse functions.
Normal Biological Roles of S100A4
In a healthy organism, S100A4 contributes to several physiological processes by regulating cellular dynamics. Its calcium-dependent interactions modulate cell motility. S100A4 interacts with components of the cytoskeleton, such as non-muscle myosin IIA, influencing cell shape changes and migration. This role in motility is important for processes like wound healing and neurite outgrowth.
S100A4 also plays a part in cell growth and differentiation. It influences protein phosphorylation and enzyme activities. Additionally, S100A4 contributes to the normal immune response and inflammation.
S100A4 in Disease Development
Dysregulation or altered expression of S100A4 is closely linked to the development and progression of various diseases. In cancer, S100A4 significantly promotes metastasis, the spread of cancer cells from the primary tumor to other parts of the body. It enhances tumor cell migration and invasiveness by influencing processes like epithelial-mesenchymal transition (EMT), where cancer cells acquire migratory properties. S100A4 can increase the stability of lamellipodia, structures involved in cell movement, and promote the secretion of matrix metalloproteinases (MMPs), enzymes that break down the extracellular matrix, facilitating invasion. High S100A4 levels are associated with poorer patient outcomes in many cancer types, including breast, lung, prostate, and colorectal cancers.
S100A4 also plays a role in fibrosis, the excessive scarring of tissues that can impair organ function. It contributes to fibrosis in organs such as the liver, kidney, and lung. In fibrotic conditions, S100A4 can activate fibroblasts, the cells responsible for producing scar tissue, leading to increased deposition of extracellular matrix components. For instance, in pulmonary fibrosis, S100A4 released by macrophages activates lung fibroblasts, promoting the disease progression. It can also amplify the pro-fibrotic effects of transforming growth factor-beta (TGF-β), a key mediator in fibrosis.
Furthermore, S100A4 is implicated in chronic inflammatory conditions, where it acts as a damage-associated molecular pattern (DAMP) that can trigger sustained inflammation. It promotes the release of pro-inflammatory cytokines and can influence immune cell function, contributing to the pathogenesis of diseases like rheumatoid arthritis and systemic sclerosis. Its ability to amplify inflammatory and fibrotic processes underscores its involvement in the destructive cycles seen in these chronic diseases. The protein’s presence in the tumor microenvironment can also influence angiogenesis, the formation of new blood vessels that support tumor growth and spread.
S100A4 as a Therapeutic Target and Biomarker
Given its widespread involvement in disease, S100A4 is being investigated as a potential therapeutic target. Researchers are exploring ways to inhibit its activity to treat conditions like cancer and fibrosis. Strategies involve developing small molecule inhibitors that can block S100A4’s interactions with other proteins, such as non-muscle myosin IIA, thereby reducing cancer cell motility and invasiveness. Inhibiting S100A4 may also interfere with its ability to regulate enzymes that degrade the extracellular matrix, further hindering disease progression. Preclinical studies have shown that S100A4 inhibitors can reduce tumor growth and metastasis in models of breast, pancreatic, and colorectal cancers.
In the context of fibrosis, suppressing S100A4 expression, release, or function is considered a promising therapeutic strategy. Studies in animal models of fibrosis have demonstrated that blocking extracellular S100A4 can mitigate or even reverse established fibrotic disease. This suggests that targeting S100A4 could offer a novel approach for anti-fibrotic treatments, particularly in conditions like systemic sclerosis.
Beyond therapeutics, S100A4 also shows promise as a biomarker for disease diagnosis, monitoring progression, and predicting patient outcomes. Elevated S100A4 levels in patient serum correlate with disease activity in several fibrotic conditions, making it a useful diagnostic and monitoring tool. For example, in idiopathic pulmonary fibrosis (IPF), higher serum S100A4 levels are associated with worse prognosis and increased mortality. In cancer, S100A4 expression in tumors and blood is often correlated with enhanced progression and metastasis, indicating its utility in predicting patient survival across various tumor types.