title: Disruption of CCL20-CCR6 interaction inhibits metastasis of advanced cutaneous T-cell lymphoma.
abstract: We recently demonstrated that upregulation of a chemokine receptor CCR6 and its ligand CCL20 led to metastasis of advanced cutaneous T-cell lymphoma (CTCL) cells, suggesting the involvement of CCL20-CCR6 interaction in initiating CTCL cell metastasis. In this study, we determined whether this interaction is functional in metastatic CTCL cells. We first demonstrated increased STAT3 expression during the progression of primary CTCL. STAT3 was spontaneously activated and mediated the transcription of CCL20 in CTCL cell lines. Next, to determine whether the transient knockdown of STAT3, CCL20, or CCR6 or treatment with neutralizing antibody against CCL20 (neutralizing CCL20 antibody) could reduce the migration ability of CTCL cells, we conducted an in vitro migration assay. All treatments reduced the nutrition-dependent migration activity of CTCL cells. Notably, treatment with neutralizing CCL20 antibody reduced the migration ability of the cells without decreasing the expression of CCL20 and CCR6. This demonstrated that the CCL20-CCR6 interaction is actually functional in metastatic CTCL cells. Finally, to examine the in vivo effect of neutralizing CCL20 antibody, we used NOD/Shi-scid IL-2γnul mice inoculated with CTCL cells. These mice were expected to die due to metastasis of CTCL cells into multiple organs. However, administration of neutralizing CCL20 antibody significantly prolonged the survival of the xenografted mice. These findings suggested that automatic activation of the STAT3/CCL20/CCR6 cascade was involved in CTCL lymphomagenesis and that disruption of CCL20-CCR6 interaction could be a key therapeutic strategy against advanced CTCL.
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitadate
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Ito
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Abe
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Nara
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Dermatology, University of Tokyo, Tokyo, Japan.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Miyagaki
authors.affiliation: Department of Dermatology, University of Tokyo, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D054399:Receptors, CCR6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D054399:Receptors, CCR6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: CCL20; CCR6; CTCL; IL-22; STAT3