期刊
SCIENCE
卷 335, 期 6064, 页码 104-108出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1211600
关键词
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资金
- NIH [R01CA102703, T32, RO1-AR044077, RO1-AR056632]
- Richard K. Gershon Research Fellowship
- National Cancer Institute of the Yale Comprehensive Cancer Center [P30 CA016359]
- Wellcome Trust
- Cancer Research UK
- Department of Health via the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre
- St. Thomas' NHS Foundation Trust
- Cancer Research UK [19309] Funding Source: researchfish
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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