Journal
BLOOD
Volume 119, Issue 20, Pages 4698-4707Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-10-386011
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Funding
- Inserm
- Ligue contre le cancer comite de l'Aude et de l'Ariege
- Association pour la Recherche sur le Cancer
- La Fondation de France
- La Fondation pour la Recherche Medicale
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Anaplastic large-cell lymphomas (ALCLs) bearing the t(2;5) translocation (ALK(+)ALCLs) are frequently characterized by skin colonization and associated with a poor prognosis. Using conditional transgenic models of anaplastic lymphoma kinase-positive (ALK(+)) lymphomas and human ALK(+)ALCL cell lines, in the present study, we show that high-mobility-group box-1 (HMGB-1), a proinflammatory cytokine, is released by ALK(+)cells, and demonstrate extracellular HMGB-1-stimulated secretion of the IL-8 chemokine by HaCaT keratinocytes through the involvement of MMP-9, PAR-2, and the NF-kappa B pathway. Furthermore, we demonstrate that, in vitro, IL-8 is able to induce the invasiveness of ALK(+)cells, which express the IL-8 receptors CXCR1 and CXCR2. In vitro and in vivo, HMGB-1 inhibition achieved by glycyrrhizin treatment led to a drastic reduction in ALK(+)cell invasiveness. The pathophysiological relevance of our observations was confirmed by demonstrating that the HMGB-1 and IL-8 receptors are expressed in ALK(+)ALCL biopsies. We have also shown that IL-8 secretion is correlated with leukemic dissemination of ALK(+)cells in a significant number of patients. The results of the present study demonstrate for the first time a relationship among the proinflammatory mediators HMGB-1, MMP-9, PAR-2, and IL-8. We propose that these mediators create a premetastatic niche within the skin, thereby participating in ALK(+)lymphoma epidermotropism. (Blood. 2012; 119(20):4698-4707)
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