Multiple reports have focused on S100A4's role in
cancer progression, specifically its ability to enhance
metastasis. However, recent studies have linked S100A4 to several diseases besides
cancer, including kidney
fibrosis,
cirrhosis,
pulmonary disease,
cardiac hypertrophy and
fibrosis,
arthritis and neuronal
injuries. Common to all these diseases is the involvement of fibrotic and inflammatory processes, i.e. processes greatly dependent on tissue remodelling, cell motility and epithelial-mesenchymal transition. Therefore, the basic
biological mechanisms behind S100A4's effects are emerging. S100A4 belongs to the S100 family of
proteins that contain two Ca2+-binding sites including a canonical EF-hand motif. S100A4 is involved in the regulation of a wide range of
biological effects including cell motility, survival, differentiation and contractility. S100A4 has both intracellular and extracellular effects. Hence, S100A4 interacts with
cytoskeletal proteins and enhances
metastasis of several types of
cancer cells. In addition, S100A4 is secreted by unknown mechanisms, thus, paracrinely stimulating a variety of cellular responses, including angiogenesis and neuronal growth. Although many cellular effects of S100A4 are well described, the molecular mechanisms whereby S100A4 elicits these responses remain largely unknown. However, it is likely that the intracellular and the extracellular effects involve distinct mechanisms. In this review, we explore the possible roles of S100A4 in non-
cancer diseases and employ this knowledge to describe underlying
biological mechanisms including a change in cellular phenotype towards less tightly adherent cells and activation of fibrotic processes that may explain this
protein's involvement in multiple pathologies.