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

Heuijoon Park; Sonali Lad; Kelsey Boland; Kelly Johnson; Nyssa Readio; Guangchun Jin; Samuel Asfaha; Kelly S. Patterson; Ashok Singh; Xiangdong Yang; Douglas Londono; Anupama Singh; Carol Trempus; Derek Gordon; Timothy C. Wang; Rebecca J. Morris

doi:10.1038/s41467-018-07688-8

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

Heuijoon Park, Sonali Lad, Kelsey Boland, Kelly Johnson, Nyssa Readio, Guangchun Jin, Samuel Asfaha, Kelly S. Patterson, Ashok Singh, Xiangdong Yang, Douglas Londono, Anupama Singh, Carol Trempus, Derek Gordon, Timothy C. Wang, Rebecca J. Morris

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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.

Original language	English (US)
Article number	5293
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07688-8
State	Published - Dec 1 2018

Bibliographical note

Funding 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.

Publisher Copyright:
© 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.

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Park, H., Lad, S., Boland, K., Johnson, K., Readio, N., Jin, G., Asfaha, S., Patterson, K. S., Singh, A., Yang, X., Londono, D., Singh, A., Trempus, C., Gordon, D., Wang, T. C., & Morris, R. J. (2018). Bone marrow-derived epithelial cells and hair follicle stem cells contribute to development of chronic cutaneous neoplasms. Nature Communications, 9(1), Article 5293. https://doi.org/10.1038/s41467-018-07688-8

Park, H, Lad, S, Boland, K, Johnson, K, Readio, N, Jin, G, Asfaha, S, Patterson, KS, Singh, A, Yang, X, Londono, D, Singh, A, Trempus, C, Gordon, D, Wang, TC & Morris, RJ 2018, 'Bone marrow-derived epithelial cells and hair follicle stem cells contribute to development of chronic cutaneous neoplasms', Nature Communications, vol. 9, no. 1, 5293. https://doi.org/10.1038/s41467-018-07688-8

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

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.",

author = "Heuijoon Park and Sonali Lad and Kelsey Boland and Kelly Johnson and Nyssa Readio and Guangchun Jin and Samuel Asfaha and Patterson, {Kelly S.} and Ashok Singh and Xiangdong Yang and Douglas Londono and Anupama Singh and Carol Trempus and Derek Gordon and Wang, {Timothy C.} and Morris, {Rebecca J.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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AU - Park, Heuijoon

AU - Lad, Sonali

AU - Boland, Kelsey

AU - Johnson, Kelly

AU - Readio, Nyssa

AU - Jin, Guangchun

AU - Asfaha, Samuel

AU - Patterson, Kelly S.

AU - Singh, Ashok

AU - Yang, Xiangdong

AU - Londono, Douglas

AU - Singh, Anupama

AU - Trempus, Carol

AU - Gordon, Derek

AU - Wang, Timothy C.

AU - Morris, Rebecca J.

N1 - Funding 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. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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

Abstract

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