[대학원 생명과학과 세미나 안내]
연사 : 박희준 박사(Fred Hutchinson Cancer Research Center)
연제 : Chronic inflammation-mediated contribution of bone marrow-derived epithelial cells and hair follicle bulge stem cells to development of cutaneous neoplasms
일시 : 2019년 9월 23일 (월) 오후 5시
장소 : 하나과학관 A동 216호
초청교수 : 지성욱 교수
Abstract
Bone marrow-derived epithelial cells (BMDECs) are recruited to sites of injury and contribute to wound healing; however, their clinical significance has not been determined in chronic inflammation-associated cutaneous malignancies such as tumors and ulcers. Here, we used gender-mismatched allogeneic bone marrow transplantation (BMT) in the context of the classical multistage murine cutaneous carcinogenesis model 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 observed that the number of cytokeratin-immunoreactive bone marrow-derived cells (BMDCs) is increased in the hyperplastic epidermis after long term treatment with TPA. Furthermore, we detected clusters of BMDCs in over 40% of papilloma samples, where they occupied 25% or more of the epithelial areas. Among the dysplastic ulcers which arose in some irradiated DMBA/TPA-treated mice, BMDCs were identified in 35% of the epithelial lesional areas in 53% of the dysplastic ulcer samples. 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, cytokeratin expression was detected by immunostaining and Q-PCR in the subset of plastic-adherent bone marrow cells (BMCs) cultured in the presence of filter-separated epidermal keratinocytes (KCs). Cytokeratin expression was increased by bone morphogenetic protein 5 (BMP5) treatment. Moreover, ex vivo invasion assays demonstrated that BMCs migrated towards the alarmin protein, High Mobility Group Box 1 (HMGB1), as well as towards epidermal KCs. Finally, naïve female mice receiving BMTs from DMBA-treated donors developed benign and malignant lesions after TPA promotion alone.We conclude that a significant number of BMDECs contribute to a subset of cutaneous papillomas and dysplastic ulcers, demonstrating a systemic contribution to these lesions. Furthermore, carcinogenexposed
BMCs can initiate benign and malignant lesions upon tumor promotion. Ultimately, these findings may suggest novel targets for treatment of non-melanoma skin cancers as well as other cancers.