Induction of Apoptotic Cell Death in Tumor Cells by S100A8/A9 Released from Inflammatory Cells Upon Cellular Activation

Polymorphonuclear neutrophils (PMNs) have received less attention than other leukocyte subsets as potential mediators of antitumor effects. However, there is a growing body of evidence that PMNs are potential mediators of antitumor effects and play an important role in the antitumor response. A protein complex S100A8/A9, formed by the two low molecular weight calcium-binding proteins S100A8 and S100A9, is released from activated PMNs and has apoptosis/ cytotoxicity-inducing activity against tumor cell lines. In this review, we focus on the molecular mechanisms by which S100A8/A9 induces apoptosis. Recent studies point to a yet undefined mechanism, probably relaying on cell surface receptor( s), by which S100A8/A9 induces apoptosis in carcinoma cell lines, in addition to zinc exclusion from target cells. Although a number of putative receptors have been identified, the cell-membrane bindings site(s) involved in the apoptosis- inducing activity of S100A8/A9 remain unknown. The identification of the binding site(s) together with the elucidation of the underlying molecular mechanisms will give new insights in how the adaptive immune system is involved in cancer regression.