title: Plasmin inhibitor reduces T-cell lymphoid tumor growth by suppressing matrix metalloproteinase-9-dependent CD11b(+)/F4/80(+) myeloid cell recruitment.
abstract: Activation of the fibrinolytic system during lymphoma progression is a well-documented clinical phenomenon. But the mechanism by which the fibrinolytic system can modulate lymphoma progression has been elusive. The main fibrinolytic enzyme, plasminogen (Plg)/plasmin (Plm), can activate matrix metalloproteinases (MMPs), such as MMP-9, which has been linked to various malignancies. Here we provide the evidence that blockade of Plg reduces T-cell lymphoma growth by inhibiting MMP-9-dependent recruitment of CD11b(+)F4/80(+) myeloid cells locally within the lymphoma tissue. Genetic Plg deficiency and drug-mediated Plm blockade delayed T-cell lymphoma growth and diminished MMP-9-dependent CD11b(+)F4/80(+) myeloid cell infiltration into lymphoma tissues. A neutralizing antibody against CD11b inhibited T-cell lymphoma growth in vivo, which indicates that CD11b(+) myeloid cells have a role in T-cell lymphoma growth. Plg deficiency in T-cell lymphoma-bearing mice resulted in reduced plasma levels of the growth factors vascular endothelial growth-A and Kit ligand, both of which are known to enhance myeloid cell proliferation. Collectively, the data presented in this study demonstrate a previously undescribed role of Plm in lymphoproliferative disorders and provide strong evidence that specific blockade of Plg represents a promising approach for the regulation of T-cell lymphoma growth.
authors.affiliation: Laboratory of Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishihara
authors.forename: C
authors.initials: C
authors.lastname: Nishida
authors.forename: Y
authors.initials: Y
authors.lastname: Tashiro
authors.forename: I
authors.initials: I
authors.lastname: Gritli
authors.forename: J
authors.initials: J
authors.lastname: Rosenkvist
authors.forename: M
authors.initials: M
authors.lastname: Koizumi
authors.forename: Y
authors.initials: Y
authors.lastname: Okaji
authors.forename: R
authors.initials: R
authors.lastname: Yamamoto
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: M
authors.initials: M
authors.lastname: Nishikori
authors.forename: K
authors.initials: K
authors.lastname: Wanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: H
authors.initials: H
authors.lastname: Nakauchi
authors.forename: B
authors.initials: B
authors.lastname: Heissig
authors.forename: K
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D039481:CD11b Antigen / Q000276:immunology*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010958:Plasminogen / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000933:Antifibrinolytic Agents; D039481:CD11b Antigen; D017931:DNA Primers; D010958:Plasminogen; D020780:Matrix Metalloproteinase 9