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The Novel Angiogenic Inhibitor, Angiocidin, Induces Differentiation of Monocytes to Macrophages

Departments of ¹ Biology and ² Neuroscience, Temple University, Philadelphia, Pennsylvania

Requests for reprints: George Tuszynski, Department of Neuroscience, 1900 North 12th Street, Philadelphia, PA 19122. Phone: 215-204-4884; Fax: 215-204-4882; E-mail: gpt{at}temple.edu.

Key Words: angiocidin • monocytes • macrophages • differentiation • angiogenesis • tumor progression • immunotherapy • cytokines

We previously showed that angiocidin, a tumor and vascular associated protein, is a potent inhibitor of angiogenesis and tumor growth. Angiocidin is a multidomain protein that exerts its antiangiogenic activity through multiple mechanisms, including effects on cell matrix interaction. Here, we describe another activity of angiocidin that may contribute to its antitumor activity. We show that angiocidin activates monocytes to secrete a mixture of proinflammatory cytokines and induces them to differentiate into macrophage-like cells. Using the monocytic cell line THP-1, we show that angiocidin induces the cells to become adherent and phagocytic, express macrophage markers, and secrete matrix metalloproteinase-9. Microarray analysis of control and angiocidin-treated THP-1 cells revealed that angiocidin up-regulated p105/p50, p100/p52, and rel B, components of the nuclear factor-B (NF-B) pathway. We confirmed the microarray data and showed that angiocidin induced phosphorylation of Iβ, p50, and p65 and translocation of p50 and p65 to the nucleus. We also showed that angiocidin activated up-stream mediators of NF-B, such as the mitogen-activated protein kinase (MAPK) pathway and phosphoinositide-3 kinase (PI3K). Blockage of NF-B and MAPK activation with small molecule inhibitors completely prevented angiocidin-mediated secretion of cytokines from THP-1 cells, but did not inhibit their adhesive phenotype. Blocking PI3K inhibited both secretion of cytokines, as well as the adhesive phenotype. These data suggest that angiocidin activates monocytes to secrete cytokines and differentiates them to a macrophage-like phenotype through at least two pathways mediated by MAPK and NF-B, as well as PI3K. [Cancer Res 2008;68(14):5905–14]