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,1
Angiogenesis Laboratory, Research Institute for Growth and Development (GROW), Departments of
* Internal Medicine and
Pathology, Maastricht University & University Hospital, Maastricht, the Netherlands;
Laboratory for Microcirculation, Cardiovascular Research Institute Maastricht, Department of Physiology, Maastricht University, Maastricht, the Netherlands; and
Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota, USA
1Correspondence: Angiogenesis Laboratory, Department of Pathology, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. E-mail: aw.griffioen{at}path.unimaas.nl
Tumor escape from immunity, as well as the failure of several anti-cancer vaccination and cellular immunotherapy approaches, is suggested to be due to the angiogenesis-mediated suppression of endothelial cell (EC) adhesion molecules involved in leukocyte-vessel wall interactions. We hypothesized that inhibition of angiogenesis would overcome this escape from immunity. We investigated this in vivo by means of intravital microscopy and ex vivo by immunohistochemistry in two mouse tumor models. Angiogenesis inhibitors anginex, endostatin, and angiostatin, and the chemotherapeutic agent paclitaxel were found to significantly stimulate leukocyte-vessel wall interactions by circumvention of EC anergy in vivo, i.e., by the up-regulation of endothelial adhesion molecules in tumor vessels. This was confirmed by in vitro studies of cultured EC at the protein and mRNA levels. The new angiostatic designer peptide anginex was most potent at overcoming EC anergy; the enhanced leukocyte-vessel interactions led to an increase in the numbers of tumor infiltrating leukocytes. While anginex inhibited tumor growth and microvessel density significantly, the amount of infiltrated leukocytes (CD45), as well as the number of CD8+ cytotoxic T lymphocytes, was enhanced markedly. The current results suggest that immunotherapy strategies can be improved by combination with anti-angiogenesis.—Dirkx, A. E. M., oude Egbrink, M. G. A., Castermans, K., van der Schaft, D. W. J., Thijssen, V. L. J. L., Dings, R. P. M., Kwee, L., Mayo, K. H., Wagstaff, J., Bouma-ter Steege, J. C. A., Griffioen, A. W. Anti-angiogenesis therapy can overcome endothelial cell anergy and promote leukocyte-endothelium interactions and infiltration in tumors.
Key Words: angiogenesis • endothelial adhesion molecules • anginex • endostatin
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