title: ALK+ALCLs induce cutaneous, HMGB-1-dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation.
abstract: 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-κB 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 pro-inflammatory 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.
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 Inserm-Université Toulouse III, Toulouse, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Dejean
authors.forename: Marianne
authors.initials: M
authors.lastname: Foisseau
authors.forename: Fréderic
authors.initials: F
authors.lastname: Lagarrigue
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
authors.forename: Naïs
authors.initials: N
authors.lastname: Prade
authors.forename: Abdelghafour
authors.initials: A
authors.lastname: Marfak
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giuriato
authors.forename: Fréderique
authors.initials: F
authors.lastname: Gaits-Iacovoni
authors.forename: Fabienne
authors.initials: F
authors.lastname: Meggetto
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D017254:Leukemic Infiltration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D055153:Stem Cell Niche / Q000235:genetics / Q000276:immunology
chemical_list: D024243:HMGB1 Protein; D016209:Interleukin-8; D016328:NF-kappa B; D044464:Receptor, PAR-2; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9