Mechanisms involved in S100A4-mediated metastatic progression. A: Molecular mechanisms associated with intracellular functions of S100A4. S100A4 is able to interact with cytoskeletal proteins, particularly nonmuscle myosin heavy chain (NMMHC) IIA, resulting in increased cell migration. In vitro studies have identified several other binding partners for S100A4 (upper right). However, the majority of these interactions have not been confirmed in vivo, and whether the interacting proteins are involved in S100A4-induced metastasis is thus mostly not known. Intracellular S100A4 expression is also associated with transcriptional regulation of certain genes, such as MMPs and E-cadherin, through so far unidentified mechanisms. Whether this could be attributed to cytoplasmic or nuclear S100A4 (or both) is also not known. Apart from the suggested functions mentioned above, the biological role of nuclear S100A4 still remains uncharacterized (question mark). B: Molecular mechanisms associated with extracellular S100A4. S100A4 is released from both tumor cells and stromal cells. Through interaction with annexin II (AII) and tissue plasminogen activator (tPA) on the surface of endothelial cells, S100A4 stimulates the conversion of plasminogen to plasmin, thus promoting angiogenesis. S100A4 also interacts with other cell surface receptors on both tumor cells and stromal cells (exemplified by a tumor cell in the figure), such as RAGE, to activate intracellular signal transduction cascades, including mitogen-activated protein kinases, increased intracellular [Ca2+], and nuclear factor-κB (see text for further details). S100A4-activated signaling pathways may, in turn, result in regulation of several target genes probably involved in stimulation of metastasis. The schematic illustrations provided in A and B are not comprehensive overviews of the molecular mechanisms of S100A4 but are illustrations of certain mechanisms associated with S100A4-induced stimulation of metastasis. C: Biological processes associated with S100A4. S100A4 stimulates cell motility, invasion, and angiogenesis and participates in the regulation of cell death. Invasion and motility is probably promoted through induction of EMT. Cell motility, invasion, and angiogenesis all contribute to stimulation of metastasis, whereas the role of S100A4-mediated regulation of cell death in cancer metastasis is so far uncertain (dashed arrow).