Figure 1.

Summary of alarmin function in the tumor microenvironment. A, in various tumor types, the β-defensins, DEFB1 and DEFB4, as well as the α-defensin, HNP-2, are down-regulated. However, when these molecules are reintroduced, they can induce apoptosis or function as chemoattractants for mDC, reinstating immunoediting. Other tumor types use DEFB4 and VEGFA to recruit mDC and initiate their incorporation into tumor vasculature, which results in tumor growth. B, breast, lung, and ovarian tumor epithelium secrete increased levels of LL-37 when compared with normal epithelial cells. In an autocrine manner, LL-37 feeds back on the tumor cells to stimulate proliferation, mediating these effects through transactivation of the EGFR or potentially, the G protein–coupled receptor, FPRL1. C, stimulated secretion of HMGB1 from tumor cells and tumor-associated macrophages or passive release by necrotic, dying tumor cells into the extracellular milieu has both protumorigenic and antitumorigenic effects. HMGB1 recruits EPCs and activates resident endothelial cells through RAGE signaling to induce angiogenesis. On the other hand, HMGB1 interacts with TLR4 on mDC to stimulate tumor antigen processing and presentation to CTLs, resulting in tumor elimination.