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.
Bibliographical noteFunding Information:
We would like to thank Todd Schuster from the FACS facility at The Hormel Institute for his support. We also thank Tia Rai and Jherek Swanger for their great help with the manuscript revision and submission. Additional help with experiments was given by Stephanie Holtorf, Aalekhya Biswas, and Samantha Skaar. This research was supported by the USA National Institutes of Health grants: NIH R01 CA097957, NIH R01 CA097957-APRC (administrative supplement to promote new collaborations), NIH R01 AR052713, and NIH R21 CA124942 to RJM. This research was also supported by DOD Discovery W81XWH-12-1-0395, a Minnesota Chemoprevention Consortium grant from the University of Minnesota Masonic Cancer Center to RJM, and by support from The Hormel Institute.
© 2018, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.