Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma.
Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.
Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA.
Badri G
BG
Modi
Jason
J
Neustadter
Elisa
E
Binda
Julia
J
Lewis
Renata B
RB
Filler
Scott J
SJ
Roberts
Bernice Y
BY
Kwong
Swapna
S
Reddy
John D
JD
Overton
Anjela
A
Galan
Robert
R
Tigelaar
Lining
L
Cai
Peter
P
Fu
Mark
M
Shlomchik
Daniel H
DH
Kaplan
Adrian
A
Hayday
Michael
M
Girardi
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004249:DNA Damage; D011905:Genes, ras; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D002273:Carcinogens; C013956:7,12-dimethylbenz(a)anthracene-dihydrodiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1