title: Mechanisms of chemical cooperative carcinogenesis by epidermal Langerhans cells.
abstract: Cutaneous squamous cell carcinoma (SCC) is the most prevalent invasive malignancy with metastatic potential. The epidermis is exposed to a variety of environmental DNA-damaging chemicals, principal among which are polyaromatic hydrocarbons (PAHs) ubiquitous in the environment, tobacco smoke, and broiled meats. Langerhans cells (LCs) comprise a network of dendritic cells situated adjacent to basal, suprabasal, and follicular infundibular keratinocytes that when mutated can give rise to SCC, and LC-intact mice are markedly more susceptible than LC-deficient mice to chemical carcinogenesis provoked by initiation with the model PAH, 7,12-dimethylbenz[a]anthracene (DMBA). LCs rapidly internalize and accumulate DMBA as numerous membrane-independent cytoplasmic foci. Repopulation of LC-deficient mice using fetal liver LC-precursors restores DMBA-induced tumor susceptibility. LC expression of p450 enzyme CYP1B1 is required for maximal rapid induction of DNA-damage within adjacent keratinocytes and their efficient neoplastic transformation; however, effects of tumor progression also attributable to the presence of LC were revealed as CYP1B1 independent. Thus, LCs make multifaceted contributions to cutaneous carcinogenesis, including via the handling and metabolism of chemical mutagens. Such findings suggest a cooperative carcinogenesis role for myeloid-derived cells resident within cancer susceptible epithelial tissues principally by influencing early events in malignant transformation.
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Lewis
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Christina D
authors.initials: CD
authors.lastname: Bürgler
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Fraser
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Haihui
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Kseniya
authors.initials: K
authors.lastname: Golubets
authors.affiliation: Greenwich Hospital, Greenwich, Connecticut, USA.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Kucher
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Renata B
authors.initials: RB
authors.lastname: Filler
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Tigelaar
authors.affiliation: Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA. Electronic address: michael.girardi@yale.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Girardi
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D065633:Cytochrome P-450 CYP1B1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007801:Langerhans Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000009:adverse effects* / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: D009153:Mutagens; D015127:9,10-Dimethyl-1,2-benzanthracene; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1