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 4

Impaired responsiveness of follicle bulge stem cells to acute induction of GLI2ΔN.

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Impaired responsiveness of follicle bulge stem cells to acute induction ...
(A) Histology of epithelial compartments in tail skin of control and K14-rtTA;tetO-GLI2ΔN (K14;GLI2ΔN) bitransgenic mice reveals basaloid cell hyperplasia in epidermis, sebaceous gland, and secondary hair germ (yellow asterisks in right panels), but not in the bulge or central isthmus (marked with black and dotted yellow bars, respectively). Original magnification, ×200 (upper panels); ×600 (lower panels). (B) Immunostaining for MYC reveals GLI2ΔN transgene expression in basal epithelial compartments, with the exception of cells in the central isthmus (white brackets). Coimmunostaining for GLI2ΔN (MYC) and PCNA reveals increased proliferation in all compartments expressing GLI2ΔN, although the fraction of PCNA+ cells is lower in the bulge than other compartments (D). Original magnification, ×200 (upper panels); ×600 (lower panels). (C) Coimmunostaining for the bulge marker K15 and PCNA confirms proliferation in bulge stem cells in tail as well as dorsal skin. Original magnification, ×400. (D) Proliferative response to GLI2ΔN is approximately 50% lower in bulge cells than in epidermal or sebaceous gland cells. (E) Progressive increase in number of Ki67+ normally quiescent bulge cells 2 and 5 days after activation of GLI2ΔN transgene expression by using doxycycline. Data in D and E are presented as mean ± SEM; *P < 0.05, **P < 0.005. (F) Increased apoptosis in bulge compartment of GLI2ΔN-expressing mice compared with controls, based on immunostaining for activated caspase-3 (arrows). Original magnification, ×600.