Mechanisms of Chemical Cooperative Carcinogenesis by Epidermal Langerhans Cells

Cutaneous squamous cell carcinoma (SCC) is the most prevalent invasive malignancy with metastatic potential. The epidermis is exposed to a variety of environmental DNA-damaging chemicals, principal among which are polyaromatic hydrocarbons (PAH) ubiquitous in the environment, tobacco smoke, and broiled meats. Langerhans cells (LC) comprise a network of dendritic cells situated adjacent to basal, suprabasal, and follicular infundibular keratinocytes that when mutated can give rise to SCC, and LC-intact mice are markedly more susceptible than LC-deficient mice to chemical carcinogenesis provoked by initiation with the model PAH, 7,12-dimethylbenz[fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][a]anthracene (DMBA). LC rapidly internalise and depot DMBA as numerous membrane-independent cytoplasmic foci. Repopulation of LC-deficient mice using foetal liver LC-precursors restores DMBA-induced tumour susceptibility. LC expression of p450 enzyme CYP1B1 is required for maximal rapid induction of DNA-damage within adjacent keratinocytes and their efficient neoplastic transformation; however, effects of tumour progression also attributable to the presence of LC were revealed as CYP1B1-independent. Thus, LC make multifaceted contributions to cutaneous carcinogenesis, including via the handling and metabolism of chemical mutagens. Such findings suggest a cooperative carcinogenesis role for myeloid-derived cells resident within cancer susceptible epithelial tissues principally by influencing early events in malignant transformation.

Authors: Lewis JM, Bürgler CD, Fraser JA, Liao H, Golubets K, Kucher CL, Zhao PY, Filler RB, Tigelaar RE, Girardi M. ;Full Source: Journal of Investigative Dermatology. 2014 Sep 18. doi: 10.1038/jid.2014.411. [Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]