Abstract LB-039: Chronic inflammation-mediated contribution of bone marrow-derived epithelial cells and hair follicle stem cells to development of cutaneous neoplasms

Bone marrow-derived epithelial cells (BMDECs) are recruited to sites of chronic inflammation; however, their clinical significance has not been determined. Here, we used gender-mismatched allogeneic bone marrow transplantation (BMT) in the context of the classical multistage model for murine cutaneous carcinogenesis to probe the recruitment of BMDECs in skin tumors initiated with the carcinogen, dimethylbenz[a]anthracene (DMBA), and promoted with the phorbol ester, 12-O-tetradecanolyphorbol-13-acetate (TPA). We detected clusters of bone marrow-derived cells (BMDCs) in over 40% of papillomas, where they occupied 25% or more of the epithelial lesional area. In the dysplastic ulcers which arose in some irradiated DMBA/TPA treated mice, the magnitude of the recruitment was greater. The BMDCs clustered in the cutaneous epithelium where they became immunoreactive to epidermal keratins, and proliferated and stratified, thereby contributing to the lesions comparably with the progeny of hair follicle stem cells in engrafted Krt1-15Cre;R26R mice. Moreover, cytokeratins were detected by immunostaining and Q-PCR in plastic adherent bone marrow cells (BMCs) cultured in the presence of filter-separated epidermal keratinocytes (KCs). Cytokeratin production was enhanced by bone morphogenetic protein 5 (BMP5). Moreover, BMCs migrated towards the alarmin protein, High Mobility Group Box 1 (HMGB1), as well as towards epidermal KCs in ex vivo invasion assays. Furthermore, when naive female mice received BMTs from donors previously treated with DMBA, several papillomas and a squamous cell carcinoma were observed after TPA promotion alone. We conclude that surprisingly large numbers of BMDECs are recruited to a subset of cutaneous papillomas and dysplastic ulcers and reflect a previously unrecognized systemic contribution to these lesions. We also conclude that carcinogen-exposed cells originating in the BMCs are sufficient to initiate a subset of benign and malignant lesions upon tumor promotion. Ultimately, these findings may provide novel targets for treatment of non-melanoma skin cancers as well as other cancers. Citation Format: Heuijoon Park, Sonali Lad, Kelsey Boland, Kelly Johnson, Nyssa Readio, Guangchun Jin, Samuel A sfaha, Kelly S. Patterson, Ashok Singh, Xiangdong Yang, Douglas Londono, Anupama Singh, Carol Trempus, Derek Gordon, Timothy C. Wang, Rebecca J. Morris. Chronic inflammation-mediated contribution of bone marrow-derived epithelial cells and hair follicle stem cells to development of cutaneous neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-039.