Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 175, Issue 4, Pages 1699-1708Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.090460
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Funding
- National Heart, Lung, and Blood Institute of the National Institutes of Health [R37 HL041002, P01 HI066105]
- La Fonclation pour la Recherche Medicale
- Terry Fox Foundation through the National Cancer Institute of Canada [TF018748]
- Deutsche Forschungsgemeinschaft [GO1360/4-1]
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Platelets are crucial regulators of tumor vascular homeostasis and continuously prevent tumor hemorrhage through secretion of their granules. However, the reason for tumor bleeding in the absence of platelets remains unknown. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. Here, we investigated the role of the inflamed tumor microenvironment in the induction of tumor vessel injury in thrombocytopenic mice. Using s.c. injections of vascular endothelial growth factor or tumor necrosis factor-a combined with depletion of neurtrophils, we demonstrate that enhancing the opening of endothelial cell junctions was not sufficient to cause bleeding in the absence of platelets; instead, induction of tissue hemorrhage in thrombocytopenia required recruitment of leukocytes. immunohistology revealed that thrombocytopenia-induced tumor hemorrhage occurs at sites of macrophage and neutrophil accumulation. Mice deficient in beta(2) or beta(3) integrins, which have decreased neutrophil and/or macrophage infiltration in their tumor stroma, were protected from thrombocytopenia-induced tumor hemorrhage, indicating that, in the absence of platelets, stroma-infiltrating leukocytes induced tumor vessel injury. This injury was independent of reactive oxygen species generation and of complement activation, as suggested by the persistence of tumor hemorrhage in C3- and nicotinamide adenine dinucleotide phosphate oxidase-deficient thrombocytopenic mice. Our results show that platelets counteract tumor-associated inflammation and that the absence of this platelet function elicits vascular injuries by tumor-infiltrating innate immune cells. (Am J Pathol 2009, 175:1699-1708; DOI: 10.2353/ajpath.2009.090460)
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