Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma

Badri G. Modi, Jason Neustadter, Elisa Binda, Julia Lewis, Renata B. Filler, Scott J. Roberts, Bernice Y. Kwong, Swapna Reddy, John D. Overton, Anjela Galan, Robert Tigelaar, Lining Cai, Peter Fu, Mark Shlomchik, Daniel H. Kaplan, Adrian Hayday, Michael Girardi

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)104-108
Number of pages5
JournalScience
Volume335
Issue number6064
DOIs
StatePublished - Jan 6 2012

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