HMGB1 Derived from Macrophages Acts as an Angiogenic Factor.

High Mobility Group Box-1 (HMGB1) protein, released from the most of necrotic cells and activated macrophages, has been identified as a novel cytokine through the receptor for advanced glycation endproducts (RAGE) and Toll-like receptor(TLR)-2 and -4. The HMGB1-RAGE and TLRs-2, -4 interactions contribute to cellular migration and the production of proinflammatory cytokines, and participate in pathomechanisms in tumor growth and invasion, in which an angiogenesis development is an important aspect.

We here show that HMGB1 stimulates the expression of Vascular Endothelial Growth Factor (VEGF), the most potent angiogenic factor in tumors, through the HMGB1-RAGE, but neither TLR-2 nor TLR-4 in macrophage-lineage cells in vitro. The mechanism of VEGF production is mediated through the Akt pathway, which is linked to tumor growth and invasion. Furthermore, HMGB1 induced angiogenesis was also observed in an in vivo rabbit corneal assay (Fig). These results suggest that HMGB1, released from the tumor-associated macrophages, may act as a key cytokine in the development of angiogenesis by producing VEGF in tumor growth and invasion. Thus the tumor-associated HMGB1/RAGE system may contribute to our understanding of the mechanism of cancer cell escape from macrophage-associated acceleration of inflammation.