Figure 8.

The functional role of neutrophils and their unique TIMP-free MMP-9 in tumor angiogenesis and tumor cell intravasation. Schema demonstrates the attraction of circulating neutrophils to the luminal surface endothelial cells activated by inflammatory stimuli produced by tumor and/or stromal cells (A), followed by neutrophil extravasation into tumor stroma (B), release of secretory granules containing prestored TIMP-free proMMP-9 from induced neutrophils (C), activation of neutrophil proMMP-9 by as yet undefined proteolytic mechanisms to produce the active MMP-9 enzyme catalytically capable of remodeling the ECM and the efficient release of ECM-sequestered angiogenic factors such as VEGF and FGF-2 (D), which in turn induce endothelial cell sprouting and formation of new blood vessels (E), intravasation of tumor cells, likely at specific entry points where ECM and endothelial basement membrane have been proteolytically modified by neutrophil MMP-9 enzyme (F), and dissemination of intravasated tumor cells via circulation (G).