Badri Modi

Date of Award

January 2012

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Michael Girardi

Subject Area(s)

Oncology, Immunology

Abstract

LANGERHANS CELLS FACILITATE MUTAGENESIS AND SQUAMOUS CELL CARCINOMA.

Badri G. Modi, Jason Neustadter, Julia Lewis, Renata Filler, Bernice Kwong, Swapna Reddy, Robert Tigelaar, Daniel Kaplan, Adrian Hayday, Michael Girardi. Department of Dermatology, Yale University, School of Medicine, New Haven, CT.

Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to model epithelial carcinogenesis. To achieve mutagenic effects, DMBA must be activated to DMBA-trans-3,4-diol via cytochrome p450 (CYP) 1B1, and this intermediate is the penultimate carcinogen responsible for inducing the signature mutation in the Hras oncogene. Recently, we observed that mice deficient in Langerhans cells (LCs), an epidermal dendritic cell (DC), are almost completely resistant to cutaneous chemical carcinogenesis, independent of alpha-beta and gamma-delta T cell influences. Investigations to identify the LC contribution to carcinogenesis revealed that DMBA-exposed LC-intact skin harbor more Hras mutations than LC-deficient skin, implying an early effect on tumor initiation. In vitro XS106 cells, a cell line derived from murine LCs, efficiently metabolized DMBA to DMBA-trans-3,4-diol as detected by liquid chromatography and tandem mass spectrometry. Moreover, initiation with DMBA-trans-3,4-diol bypassed tumor resistance and restored tumorigenesis in LC-deficient mice. Consistent with previous reports,

murine and human LCs expressed a higher CYP1B1:CYP1A1 ratio than keratinocytes, conferring an advantage in the ability to metabolize to mutagenic intermediates. Thus, our data suggest a cooperative carcinogenesis scenario in which LC generate DMBA trans-3,4-diol which moves into keratinocytes for further metabolism and mutagenesis.

Tissue-associated DCs - which are also found in other epithelial surfaces - can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

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This is an Open Access Thesis.

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