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Abstract
We used allogeneic bone marrow transplantation (BMT) and a mouse multistage cutaneous carcinogenesis model to probe recruitment of bone marrow-derived epithelial cells (BMDECs) in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with 12-O-tetradecanolyphorbol-13-acetate (TPA). BMDECs clustered in the lesional epithelium, expressed cytokeratins, proliferated, and stratified. We detected cytokeratin induction in plastic-adherent bone marrow cells (BMCs) cultured in the presence of filter-separated keratinocytes (KCs) and bone morphogenetic protein 5 (BMP5). Lineage-depleted BMCs migrated towards High Mobility Group Box 1 (HMGB1) protein and epidermal KCs in ex vivo invasion assays. Naive female mice receiving BMTs from DMBA-treated donors developed benign and malignant lesions after TPA promotion alone. We conclude that BMDECs contribute to the development of papillomas and dysplasia, demonstrating a systemic contribution to these lesions. Furthermore, carcinogen-exposed BMCs can initiate benign and malignant lesions upon tumor promotion. Ultimately, these findings may suggest targets for treatment of non-melanoma skin cancers.
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1 Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Department of Dermatology, Columbia University, New York, NY, USA; Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Center, Columbia University, New York, NY, USA; The Hormel Institute, University of Minnesota, Austin, MN, USA
2 The Hormel Institute, University of Minnesota, Austin, MN, USA
3 Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Center, Columbia University, New York, NY, USA
4 Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
5 Matrix Biology Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
6 Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; Department of Dermatology, Columbia University, New York, NY, USA; The Hormel Institute, University of Minnesota, Austin, MN, USA