Bone marrow-derived epithelial cells and hair follicle stem cells contribute to development of chronic cutaneous neoplasms

Nat Commun. 2018 Dec 13;9(1):5293. doi: 10.1038/s41467-018-07688-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / pathology*
  • Bone Marrow Transplantation
  • Bone Morphogenetic Protein 5 / metabolism
  • Cell Movement
  • Cell Plasticity / physiology
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / pathology*
  • Coculture Techniques
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology*
  • Female
  • HMGB1 Protein / metabolism
  • Hair Follicle / cytology
  • Keratinocytes / pathology
  • Keratins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness / pathology
  • Papilloma / pathology
  • Skin Neoplasms / pathology*
  • Stem Cells / cytology
  • Stem Cells / pathology
  • Tetradecanoylphorbol Acetate / toxicity
  • Tumor Cells, Cultured

Substances

  • Bmp5 protein, mouse
  • Bone Morphogenetic Protein 5
  • HMGB1 Protein
  • HMGB1 protein, mouse
  • 9,10-Dimethyl-1,2-benzanthracene
  • Keratins
  • Tetradecanoylphorbol Acetate