Damage-associated molecular patterns (DAMPs) and mesenchymal stem cells: A matter of attraction and excitement

Necrotic cell death is a typical feature of solid tumors leading to the release of necrotic products, also known as damage-associated molecular patterns (DAMPs), that enhance angiogenesis and prime the immune response. Among the DAMPs, particular attention has been focused on the DNA-binding molecule high-mobility group box 1 (HMGB-1) that can act as a chemoattractant and activator of granulocytes. Here, we discuss an article in this issue of the European Journal of Immunology that demonstrates that DAMPs promote both proliferation and trafficking of mesenchymal stem cells (MSCs), identifying HMGB-1 as a key factor in the regulation of these processes. Moreover, the study shows that DAMPs interfere with the expression of the immunosuppressive molecule indoleamine-2,3-dioxygenase in MSCs, and that the biological activity of HMGB-1 toward MSCs is abolished when HMGB-1 is oxidized. Based on the data from this, and other studies, we depict a model in which DAMPs released from necrotic tumor cells attract and stimulate local proliferation of MSCs that differentiate into tumor-associated fibroblasts promoting tumor growth and angiogenesis. Importantly, the hypoxic conditions of the tumor microenvironment may protect DAMPs from oxidation and thereby preserve their functionality.