Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations
Marina Grachtchouk, … , Monique Verhaegen, Andrzej A. Dlugosz
Marina Grachtchouk, … , Monique Verhaegen, Andrzej A. Dlugosz
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):1768-1781. https://doi.org/10.1172/JCI46307.
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Research Article

Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations

Abstract

Uncontrolled Hedgehog (Hh) signaling leads to the development of basal cell carcinoma (BCC), the most common human cancer, but the cell of origin for BCC is unclear. While Hh pathway dysregulation is common to essentially all BCCs, there exist multiple histological subtypes, including superficial and nodular variants, raising the possibility that morphologically distinct BCCs may arise from different cellular compartments in skin. Here we have shown that induction of a major mediator of Hh signaling, GLI2 activator (GLI2ΔN), selectively in stem cells of resting hair follicles in mice, induced nodular BCC development from a small subset of cells in the lower bulge and secondary hair germ compartments. Tumorigenesis was markedly accelerated when GLI2ΔN was induced in growing hair follicles. In contrast, induction of GLI2ΔN in epidermis led to the formation of superficial BCCs. Expression of GLI2ΔN at reduced levels in mice yielded lesions resembling basaloid follicular hamartomas, which have previously been linked to low-level Hh signaling in both mice and humans. Our data show that the cell of origin, tissue context (quiescent versus growing hair follicles), and level of oncogenic signaling can determine the phenotype of Hh/Gli-driven skin tumors, with high-level signaling required for development of superficial BCC-like tumors from interfollicular epidermis and nodular BCC-like tumors from hair follicle stem cells.

Authors

Marina Grachtchouk, Joanna Pero, Steven H. Yang, Alexandre N. Ermilov, L. Evan Michael, Aiqin Wang, Dawn Wilbert, Rajiv M. Patel, Jennifer Ferris, James Diener, Mary Allen, Seokchun Lim, Li-Jyun Syu, Monique Verhaegen, Andrzej A. Dlugosz

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Figure 8

Low-level expression of GLI2ΔN gives rise to basaloid hamartomas instead of nodular BCC-like tumors.

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Low-level expression of GLI2ΔN gives rise to basaloid hamartomas instead...
(A) Histology showing nodular BCC-like tumors in iK5;rtTA;GLI2ΔN mouse treated with 1 gm/kg doxycycline in chow and 200 μg/ml doxycycline in drinking water (GLI2ΔN-high), compared with basaloid hamartomas in K5;rtTA;GLI2ΔN mice treated with 2 μg/ml doxycycline (GLI2ΔN-low) in drinking water, which resemble lesions that arise in mice harboring a Cre-inducible M2SMO allele (SMO). (B) Ki67 reveals limited proliferation at the periphery of basaloid hamartomas arising in GLI2ΔN-low and SMO mice, compared with diffuse proliferation in nodular BCCs in GLI2ΔN-high mice. Dashed lines in right panels outline the extent of epithelial cells comprising hamartomas. HF indicates an anagen hair follicle matrix with robust Ki67 immunostaining. (C) MYC immunostaining to detect GLI2ΔN confirms low-level expression in GLI2ΔN-low mice. Original magnification, ×200 (A–C).