TY - JOUR
T1 - Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma
AU - Modi, Badri G.
AU - Neustadter, Jason
AU - Binda, Elisa
AU - Lewis, Julia
AU - Filler, Renata B.
AU - Roberts, Scott J.
AU - Kwong, Bernice Y.
AU - Reddy, Swapna
AU - Overton, John D.
AU - Galan, Anjela
AU - Tigelaar, Robert
AU - Cai, Lining
AU - Fu, Peter
AU - Shlomchik, Mark
AU - Kaplan, Daniel H.
AU - Hayday, Adrian
AU - Girardi, Michael
PY - 2012/1/6
Y1 - 2012/1/6
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1211600
DO - 10.1126/science.1211600
M3 - Article
C2 - 22223807
AN - SCOPUS:84855487102
SN - 0036-8075
VL - 335
SP - 104
EP - 108
JO - Science
JF - Science
IS - 6064
ER -
