Department of Pathology and Cell Biology, Columbia University, New York, 10032, NY, USA.
Department of Dermatology, Columbia University, New York, 10032, NY, USA.
Nat Commun. 2018 Dec 13;9(1):5293. doi: 10.1038/s41467-018-07688-8.
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.
我们使用异基因骨髓移植（BMT）和小鼠多阶段皮肤致癌模型，探究在二甲基苯并[a]蒽（DMBA）引发的皮肤肿瘤和 12-O-十四烷酰佛波醇-13-乙酸酯（TPA）促进下，骨髓来源的上皮细胞（BMDECs）在皮肤肿瘤中的募集情况。BMDECs 在病变上皮中聚集，表达细胞角蛋白，增殖并分层。我们在存在经滤器分离的角质形成细胞（KCs）和骨形态发生蛋白 5（BMP5）的情况下，检测到塑料贴附的骨髓细胞（BMCs）中细胞角蛋白的诱导。在体外侵袭实验中，耗尽谱系的 BMCs 向高迁移率族蛋白 1（HMGB1）蛋白和表皮 KC 迁移。在单独接受 TPA 促进后，接受来自 DMBA 处理供体的 BMT 的雌性小鼠发展出良性和恶性病变。我们得出结论，BMDECs 有助于乳头瘤和发育不良的发展，表明它们对这些病变有全身性贡献。此外，暴露于致癌剂的 BMCs 在肿瘤促进后可引发良性和恶性病变。最终，这些发现可能提示了治疗非黑色素瘤皮肤癌的靶点。
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