title: Possible mechanisms of the crosstalk between Langerhans cells and regulatory T cells in extramammary Paget disease by receptor activator of nuclear factor kappa B (RANK) ligand/RANK pathways.
abstract: BACKGROUND
  Extramammary Paget disease (EMPD) is a skin adenocarcinoma of apocrine gland origin, in which Paget cells express receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) and matrix metalloproteinase (MMP)-7, and release soluble (s)RANKL into the tumour microenvironment. We previously reported that about 60% of the RANK+cells among the stromal cells are M2 macrophages, but the identity of the remaining population of RANK+cells is still unknown.
  
  
  OBJECTIVE
  To investigate the unknown subpopulation of RANK-expressing cells in EMPD.
  
  
  METHODS
  The main population of RANK-expressing cells in the epidermis was composed of epidermal Langerhans cells (LCs). To explore the effects of RANKL on LCs, we stimulated LCs generated from human CD34+hematopoietic progenitor cells with graded concentrations of sRANKL. To further examine the correlation between LCs and regulatory T cells (Tregs) in EMPD, we employed immunohistochemical staining.
  
  
  RESULTS
  sRANKL stimulation was shown to augment the production of C-C motif chemokine ligand 17 (CCL17) from LCs. We additionally demonstrated CCL17 expression by CD1a+LCs in EMPD in an immunofluorescence study. Spearman's rank correlation test confirmed a correlation between the number of LCs and the number of Foxp3+Tregs in the lesional skin of invasive EMPD. In addition, the numbers of Foxp3+Tregs in the sentinel lymph nodes of metastatic EMPD were significantly higher than those of metastatic melanoma, which did not express RANKL.
  
  
  CONCLUSIONS
  The findings suggest that the RANKL/RANK pathway in EMPD might contribute to the recruitment of Tregs and to maintenance of the tumour microenvironment.
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujimura
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kambayashi
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Furudate
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kakizaki
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hidaka
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Aiba
mesh_terms: D054414:Chemokine CCL17 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007801:Langerhans Cells / Q000502:physiology*; D008207:Lymphatic Metastasis; D016328:NF-kappa B / Q000378:metabolism*; D010145:Paget Disease, Extramammary / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D054414:Chemokine CCL17; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D053245:RANK Ligand