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Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis

Oncogene volume 32, pages 3732–3743 (2013)Cite this article

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Abstract

Epidermal keratinocytes and hair follicle (HF) stem cells (SCs) expressing oncogenes are competent at developing squamous cell carcinomas (SCCs) in epidermis and HFs, respectively. To determine whether bulge and hair germ (HG) SCs from HF contribute to SCC generation at distant epidermis, the most frequent epidermal region where these lesions arise in human skin, we used a skin cancer mouse model expressing E6 and E7 oncoproteins from Human papillomavirus (HPV) 16 in SCs and basal keratinocytes. This previously described mouse model recapitulates the human skin papillomavirus-induced SCC pathology. We show that E6 and E7 expression promote the expansion of keratin 15 (K15)-expressing cells. These K15+ aberrant cells exhibit some HGSC markers and diminished expression of Tcf3 and Sox9 hair SC specification genes, which are accumulated in HFs and mislocalized to interfollicular epidermis. Leucine-rich G-protein-coupled receptor 5 (Lgr5)-expressing SCs, localized in the bulge and HG, are the origin of the expanded K15+ cell population. A large subset of the Lgr5+ SC progeny, expressing K15 and P-cadherin, is aberrantly mobilized to the upper region of HFs and the epidermis, and accumulates at E6/E7-induced pre-neoplastic lesions and epidermal tumors. These findings indicate that aberrant accumulation of altered SCs in HFs and their subsequent migration to the epidermis contribute to HPV-induced tumor development.

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Acknowledgements

We thank D Hanahan and JM Arbeit (NCI MMHCC Repository) for the K14-HPV16 mice, A Villanueva for helpful advice, S Gonzalo for critical reading of the manuscript, R Alvarez, J Comas and E Castaño (Universitat de Barcelona-SCT) for their technical support in flow cytometry and the IDIBELL animal facility service for mouse care. VdSD is funded by a Spanish Ministry of Science and Innovation fellowship, SSS is funded by a Spanish Ministry of Education fellowship and DRA and AVG received an IDIBELL fellowship. The research of PM’s group is supported by the Spanish Ministry of Science and Innovation (SAF2008-01173) and by the Catalan Department of Health (Generalitat de Catalunya).

Author contributions: Conception and design was provided by VdSD, SSS, DRA and PM. Collection and assembly of data was performed by VdSD, SSS, DRA, AVG, MU, RMP and GP. Data analysis and interpretation was done by VdSD, SSS, DRA, AVG, MU, RMP, GP, EGS, OC, FV, JMP, EB and PM. The manuscript was written by PM.

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Authors and Affiliations

  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

    V da Silva-Diz, S Solé-Sánchez, A Valdés-Gutiérrez, M Urpí, D Riba-Artés, E González-Suárez & P Muñoz

  2. Pathology Service, Hospital Universitario de Bellvitge/IDIBELL, Barcelona, Spain

    R M Penin

  3. Department of Cell Differentiation and Cancer, Center for Genomic Research (CRG), Biomedical Research Park (PRBB), Barcelona, Spain

    G Pascual

  4. Translational Research Laboratory, Catalan Institute of Oncology (ICO/IDIBELL), Barcelona, Spain

    O Casanovas & F Viñals

  5. Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques II, Universitat de Barcelona-IDIBELL, Barcelona, Spain

    F Viñals

  6. Molecular Oncology Unit, Centro de Invstigaciones Energéticas Medioambientales y Tencológicas, Madrid, Spain

    J M Paramio

  7. Oncology Program, Institute for Research in Biomedicine (IRB), Barcelona, Spain

    E Batlle

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da Silva-Diz, V., Solé-Sánchez, S., Valdés-Gutiérrez, A. et al. Progeny of Lgr5-expressing hair follicle stem cell contributes to papillomavirus-induced tumor development in epidermis. Oncogene 32, 3732–3743 (2013). https://doi.org/10.1038/onc.2012.375

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