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Blood, 1 January 2006, Vol. 107, No. 1, pp. 317-327.
Prepublished online as a Blood First Edition Paper on September 20, 2005; DOI 10.1182/blood-2005-04-1458.
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Submitted April 11, 2005
Accepted August 24, 2005
Pro-angiogenic role of neutrophil-like inflammatory heterophils during neovascularization induced by growth factors and human tumor cells
Andries Zijlstra, Marco Seandel, Tatyana A Kupriyanova, Juneth J Partridge, Mark A Madsen, Elizabeth A Hahn-Dantona, James P Quigley, and Elena I Deryugina*
Cell Biology, Scripps Research Institute, La Jolla, CA, USA
Medicine, Memorial Sloan Kettering, New York, New York, USA
Vascular Biology, American Red Cross, Rockville, MD, USA
* Corresponding author; email: deryugin{at}scripps.edu.
A quantitative in vivo angiogenesis model employing collagen onplants placed on the chick embryo chorioallantoic membrane (CAM) has been used in this study to assess the spatial and temporal associations between neutrophil-like inflammatory cells, namely chicken heterophils, and the development of new blood vessels. Previously we have demonstrated that monocytes/macrophages infiltrating the onplants were associated with extracellular matrix remodeling and angiogenesis, in particular by delivering MMP-13 collagenase. By introducing chicken gelatinase B (chMMP-9) as a specific marker for heterophils, we now show that the onset and extent of angiogenesis induced by purified growth factors or by human HT-1080 fibrosarcoma cells correlated with the initial influx of chMMP-9-positive heterophils. This early heterophil arrival was followed by the infiltration of monocytes/macrophages and appeared to sustain further blood vessel formation. The disruption of inflammatory cell influx by two mechanistically distinct anti-inflammatory drugs cortisone and ibuprofen significantly inhibited angiogenesis, indicating a functional involvement of these inflammatory cells in new blood vessel development. A direct addition of isolated heterophils or purified chMMP-9 into the HT-1080-onplants engrafted into cortisone- or ibuprofen-treated embryos reversed the anti-angiogenic effects of the drugs. The exogenously-added heterophils induced in vivo a further infiltration of endogenous heterophils and monocytes and dramatically rescued the impaired angiogenesis, highlighting the importance of early inflammatory leukocytes in tumor-induced angiogenesis. Moreover, purified heterophils incorporated into onplants lacking growth factors or tumor cells, induced angiogenesis in non-treated embryos, further indicating a direct pro-angiogenic role for neutrophil-like leukocytes.
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